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  • Herpesvirus membrane fusion – a team effort
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2020-01-11
    Benjamin Vollmer; Kay Grünewald

    One of the essential steps in every viral ‘life’ cycle is entry into the host cell. Membrane-enveloped viruses carry dedicated proteins to catalyse the fusion of the viral and cellular membrane. Herpesviruses feature a set of essential, structurally diverse glycoproteins on the viral surface that form a multicomponent fusion machinery, necessary for the entry mechanism. For Herpes simplex virus 1, these essential glycoproteins are gD, gH, gL and gB. In this review we describe the functions of the individual components, the potential interactions between them as well as the influence of post-translational modifications on the fusion mechanism.

    更新日期:2020-01-13
  • Emerging patterns of tyrosine sulfation and O-glycosylation cross-talk and co-localization
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2020-01-09
    Akul Y Mehta; Jamie Heimburg-Molinaro; Richard D Cummings; Christoffer K Goth
    更新日期:2020-01-09
  • Nucleosomes as allosteric scaffolds for genetic regulation
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2020-01-03
    Shoji Takada; Giovanni B Brandani; Cheng Tan

    Nucleosomes are stable yet highly dynamic complexes exhibiting diverse types of motions, such as sliding, DNA unwrapping, and disassembly, encoding a landscape with a large number of metastable states. In this review, describing recent studies on these nucleosome structure changes, we propose that the nucleosome can be viewed as an ideal allosteric scaffold: regulated by effector molecules such as transcription factors and chromatin remodelers, the nucleosome controls the downstream gene activity. Binding of transcription factors to the nucleosome can enhance DNA unwrapping or slide the DNA, altering either the binding or the unbinding of other transcription factors to nearby sites. ATP-dependent chromatin remodelers induce a series of DNA deformations, which allosterically propagate throughout the nucleosome to induce DNA sliding or histone exchange.

    更新日期:2020-01-04
  • Mannosidase mechanism: at the intersection of conformation and catalysis
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-12-28
    Carme Rovira; Alexandra Males; Gideon J Davies; Spencer J Williams

    Mannosidases are a diverse group of enzymes that are important in the biological processing of mannose-containing polysaccharides and complex glycoconjugates. They are found in 12 of the >160 sequence-based glycosidase families. We discuss evidence that nature has evolved a small set of common mechanisms that unite almost all of these mannosidase families. Broadly, mannosidases (and the closely related rhamnosidases) perform catalysis through just two conformations of the oxocarbenium ion-like transition state: a B2,5 (or enantiomeric 2,5B) boat and a 3H4 half-chair. This extends to a new family (GT108) of GDPMan-dependent β-1,2-mannosyltransferases/phosphorylases that perform mannosyl transfer through a boat conformation as well as some mannosidases that are metalloenzymes and require divalent cations for catalysis. Yet, among this commonality lies diversity. New evidence shows that one unique family (GH99) of mannosidases use an unusual mechanism involving anchimeric assistance via a 1,2-anhydro sugar (epoxide) intermediate.

    更新日期:2019-12-29
  • Antibody recognition of bacterial surfaces and extracellular polysaccharides
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-12-23
    Caroline Soliman; Gerald B Pier; Paul A Ramsland
    更新日期:2019-12-25
  • Recent advances in glycoinformatic platforms for glycomics and glycoproteomics
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-12-23
    Jodie L Abrahams; Ghazaleh Taherzadeh; Gabor Jarvas; Andras Guttman; Yaoqi Zhou; Matthew P Campbell

    Protein glycosylation is the most complex and prevalent post-translation modification in terms of the number of proteins modified and the diversity generated. To understand the functional roles of glycoproteins it is important to gain an insight into the repertoire of oligosaccharides present. The comparison and relative quantitation of glycoforms combined with site-specific identification and occupancy are necessary steps in this direction. Computational platforms have continued to mature assisting researchers with the interpretation of such glycomics and glycoproteomics data sets, but frequently support dedicated workflows and users rely on the manual interpretation of data to gain insights into the glycoproteome. The growth of site-specific knowledge has also led to the implementation of machine-learning algorithms to predict glycosylation which is now being integrated into glycoproteomics pipelines. This short review describes commercial and open-access databases and software with an emphasis on those that are actively maintained and designed to support current analytical workflows.

    更新日期:2019-12-25
  • Structural glycobiology in the age of electron cryo-microscopy
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-12-23
    Mihaela Atanasova; Haroldas Bagdonas; Jon Agirre
    更新日期:2019-12-25
  • Structure and engineering of tandem repeat lectins
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-12-13
    Simona Notova; François Bonnardel; Frédérique Lisacek; Annabelle Varrot; Anne Imberty

    Through their ability to bind complex glycoconjugates, lectins have unique specificity and potential for biomedical and biotechnological applications. In particular, lectins with short repeated peptides forming carbohydrate-binding domains are not only of high interest for understanding protein evolution but can also be used as scaffold for engineering novel receptors. Synthetic glycobiology now provides the tools for engineering the specificity of lectins as well as their structure, multivalency and topologies. This review focuses on the structure and diversity of two families of tandem-repeat lectins, that is, β-trefoils and β-propellers, demonstrated as the most promising scaffold for engineering novel lectins.

    更新日期:2019-12-13
  • Allostery in C-type lectins
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-12-13
    Bettina G Keller; Christoph Rademacher

    C-type lectins are the largest and most diverse family of mammalian carbohydrate-binding proteins. They share a common protein fold, which provides the unifying basis for calcium-mediated carbohydrate recognition. Their involvement in a multitude of biological functions is remarkable. Here, we review the variety of tasks these lectins are involved in alongside with the structural demands on the overall protein architecture. Subtle changes of the protein structure are implemented to cope with such diverse functional requirements. The presence of a high level of structural dynamics over a broad palette of time scales is paired with the presence of secondary binding sites and allosteric coordination of remote sites and renders this lectin fold a highly adaptable scaffold.

    更新日期:2019-12-13
  • Glycan structures and their interactions with proteins. A NMR view
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-12-10
    Ana Gimeno, Pablo Valverde, Ana Ardá, Jesús Jiménez-Barbero

    Carbohydrate molecules are essential actors in key biological events, being involved as recognition points for cell–cell and cell–matrix interactions related to health and disease. Despite outstanding advances in cryoEM, X-ray crystallography and NMR still remain the most employed techniques to unravel their conformational features and to describe the structural details of their interactions with biomolecular receptors. Given the intrinsic flexibility of saccharides, NMR methods are of paramount importance to deduce the extent of motion around their glycosidic linkages and to explore their receptor-bound conformations. We herein present our particular view on the latest advances in NMR methodologies that are permitting to magnify their applications for deducing glycan conformation and dynamics and understanding the recognition events in which there are involved.

    更新日期:2019-12-11
  • Intrinsic dynamics is evolutionarily optimized to enable allosteric behavior
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-27
    Yan Zhang, Pemra Doruker, Burak Kaynak, She Zhang, James Krieger, Hongchun Li, Ivet Bahar

    Allosteric behavior is central to the function of many proteins, enabling molecular machinery, metabolism, signaling and regulation. Recent years have shown that the intrinsic dynamics of allosteric proteins defined by their 3-dimensional architecture or by the topology of inter-residue contacts favors cooperative motions that bear close similarity to structural changes they undergo during their allosteric actions. These conformational motions are usually driven by energetically favorable or soft modes at the low frequency end of the mode spectrum, and they are evolutionarily conserved among orthologs. These observations brought into light evolutionary adaptation mechanisms that help maintain, optimize or regulate allosteric behavior as the evolution from bacterial to higher organisms introduces sequential heterogeneities and structural complexities.

    更新日期:2019-11-28
  • Dynamic multivalent interactions of intrinsically disordered proteins
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-26
    Jingwei Weng, Wenning Wang

    Protein–protein interactions involving intrinsically disordered proteins (IDPs) usually display dynamic and multivalent features. Recent experimental data revealed myriad functional roles of the dynamic multivalent interaction (DMI) of IDPs. However, characterization of DMI remains a challenge due to its complex and promiscuous nature. Recent studies start showing that understanding the mechanistic role of DMI relies on combined use of various techniques and construction of microscopic models in elucidating the binding thermodynamics and kinetics.

    更新日期:2019-11-27
  • Chromatin structure changes during various processes from a DNA sequence view
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-22
    Hui Quan, Ying Yang, Sirui Liu, Hao Tian, Yue Xue, Yi Qin Gao

    Chromatin mainly consists of protein and DNA, and the sequence information of DNA contributes to controlling the spatial structure of chromatin. Genome-wide contact patterns of chromosome at high precision uncover fine structural properties, conductive to exploring underlying mechanisms on structure establishment and function realization for chromatin. In this short review, we describe changes of chromatin structure during various biological processes from a DNA sequence view, with an increase of the overall domain segregation from birth to senescence and establishment of cell identity related cross-domain contacts. Segregation patterns vary with cell stage and genomic distance. Meanwhile, possible effects of cell cycle, temperature, nuclear lamina and nucleolus on chromatin structure are discussed. At last, important roles of transcription factors and other proteins in proper chromatin organization are also discussed.

    更新日期:2019-11-26
  • Recent insights into the structure of TFIID, its assembly, and its binding to core promoter
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-18
    Avinash B Patel, Basil J Greber, Eva Nogales

    TFIID is a large multiprotein assembly that serves as a general transcription factor for transcription initiation by eukaryotic RNA polymerase II (Pol II). TFIID is involved in the recognition of the core promoter sequences and neighboring chromatin marks, and can interact with gene-specific activators and repressors. In order to obtain a better molecular and mechanistic understanding of the function of TFIID, its structure has been pursued for many years. However, the scarcity of TFIID and its highly flexible nature have made this pursuit very challenging. Recent breakthroughs, largely due to methodological advances in cryo-electron microscopy, have finally described the structure of this complex, both alone and engaged with core promoter DNA, revealing the functional significance of its conformational complexity in the process of core promoter recognition and initiation of Pol II transcription. Here, we review these recent structural insights and discuss their implications for our understanding of eukaryotic transcription initiation.

    更新日期:2019-11-19
  • Peptidyl arginine deiminases: detection and functional analysis of protein citrullination
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-03-01
    Ronak Tilvawala, Paul R Thompson

    Citrullination is a post-translational modification of arginine that is catalyzed by the protein arginine deiminases (PADs). Abnormal citrullination is observed in many autoimmune diseases and cancers. Anti-citrullinated protein antibodies (ACPA) are hallmarks of RA and used as diagnostic markers for disease diagnosis. Even though citrullination is associated with many different pathologies, its role remains unclear due to the challenges associated with the detection of citrullinated proteins since the mass change is only 0.984 Da. Moreover, the functional effects of protein citrullination remain mostly unknown. Herein, we discuss a brief overview of PAD structure and function, recent advances in the detection of citrullinated proteins in complex biological systems and the functional consequences of protein citrullination.

    更新日期:2019-11-18
  • Structural biology of multicomponent assemblies in DNA double-strand-break repair through non-homologous end joining
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-14
    Amanda K Chaplin, Tom L Blundell

    The mechanisms mediating the repair of DNA damage in human cells have been the focus of a multitude of studies since the middle of the previous century, and many of the proteins implicated in these processes have been identified as being part of large macromolecular assemblies. This review gives an overview of the current knowledge of protein structures specifically involved in the repair of DNA double strand breaks through Non-Homologous End Joining, with a focus on recent structures obtained via cryo-electron microscopy and prospects for how this rapidly evolving method will impact our understanding of DNA repair.

    更新日期:2019-11-14
  • Transcription through the nucleosome.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : null
    Tomoya Kujirai,Hitoshi Kurumizaka

    Eukaryotic genomic DNA is wrapped around the histone octamer and forms the nucleosome, which is the basic unit of chromatin. Nevertheless, eukaryotic RNA polymerases transcribe the DNA that is tightly bound to the histone core in the nucleosome. For transcription to proceed on the nucleosome, the RNA polymerases must overcome the tight contacts between histones and DNA during transcription elongation. Here, we review the structural and biochemical studies of the transcription mechanism on the nucleosome, and focus on recent information to understand how RNA polymerases transcribe the genomic DNA in chromatin.

    更新日期:2019-11-01
  • Molecular structure in biomolecular condensates.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : null
    Ivan Peran,Tanja Mittag

    Evidence accumulated over the past decade provides support for liquid-liquid phase separation as the mechanism underlying the formation of biomolecular condensates, which include not only 'membraneless' organelles such as nucleoli and RNA granules, but additional assemblies involved in transcription, translation and signaling. Understanding the molecular mechanisms of condensate function requires knowledge of the structures of their constituents. Current knowledge suggests that structures formed via multivalent domain-motif interactions remain largely unchanged within condensates. Two different viewpoints exist regarding structures of disordered low-complexity domains within condensates; one argues that low-complexity domains remain largely disordered in condensates and their multivalency is encoded in short motifs called 'stickers', while the other argues that the sequences form cross-β structures resembling amyloid fibrils. We review these viewpoints and highlight outstanding questions that will inform structure-function relationships for biomolecular condensates.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Editorial overview: Protein-nucleic acid interactions - cryo-EM, what else?
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-10-23
    Frédéric H-T Allain,Martin Jinek

    更新日期:2019-11-01
  • Mechanisms of replication origin licensing: a structural perspective.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-10-21
    Franziska Bleichert

    The duplication of chromosomal DNA is a key cell cycle event that involves the controlled, bidirectional assembly of the replicative machinery. In a tightly regulated, multi-step reaction, replicative helicases and other components of the DNA synthesis apparatus are recruited to replication start sites. Although the molecular approaches for assembling this machinery vary between the different domains of life, a common theme revolves around the use of ATP-dependent initiation factors to recognize and remodel origins and to load replicative helicases in a bidirectional manner onto DNA. This review summarizes recent advances in understanding the mechanisms of replication initiation in eukaryotes, focusing on how the replicative helicase is loaded in this system.

    更新日期:2019-11-01
  • PARP family enzymes: regulation and catalysis of the poly(ADP-ribose) posttranslational modification.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2018-11-28
    Marie-France Langelier,Travis Eisemann,Amanda A Riccio,John M Pascal

    Poly(ADP-ribose) is a posttranslational modification and signaling molecule that regulates many aspects of human cell biology, and it is synthesized by enzymes known as poly(ADP-ribose) polymerases, or PARPs. A diverse collection of domain structures dictates the different cellular roles of PARP enzymes and regulates the production of poly(ADP-ribose). Here we primarily review recent structural insights into the regulation and catalysis of two family members: PARP-1 and Tankyrase. PARP-1 has multiple roles in the cellular response to DNA damage and the regulation of gene transcription, and Tankyrase regulates a diverse set of target proteins involved in cellular processes such as mitosis, genome integrity, and cell signaling. Both enzymes offer interesting modes of regulating the production and the target site selectivity of the poly(ADP-ribose) modification.

    更新日期:2019-11-01
  • Structural gymnastics of RAG-mediated DNA cleavage in V(D)J recombination.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2018-11-27
    Heng Ru,Pengfei Zhang,Hao Wu

    A hallmark of vertebrate immunity is the diverse repertoire of antigen-receptor genes that results from combinatorial splicing of gene coding segments by V(D)J recombination. The (RAG1-RAG2)2 endonuclease complex (RAG) specifically recognizes and cleaves a pair of recombination signal sequences (RSSs), 12-RSS and 23-RSS, via the catalytic steps of nicking and hairpin formation. Both RSSs immediately flank the coding end segments and are composed of a conserved heptamer, a conserved nonamer, and a non-conserved spacer of either 12 base pairs (bp) or 23 bp in between. A single RAG complex only synapses a 12-RSS and a 23-RSS, which was denoted the 12/23 rule, a dogma that ensures recombination between V, D and J segments, but not within the same type of segments. This review recapitulates current structural studies to highlight the conformational transformations in both the RAG complex and the RSS during the consecutive steps of catalysis. The emerging structural mechanism emphasizes distortion of intact RSS and nicked RSS exerted by a piston-like motion in RAG1 and by dimer closure, respectively. Bipartite recognition of heptamer and nonamer, flexibly linked nonamer-binding domain dimer relatively to the heptamer recognition region dimer, and RSS plasticity and bending by HMGB1 together contribute to the molecular basis of the 12/23 rule in the RAG molecular machine.

    更新日期:2019-11-01
  • A structural view of the initiators for chromosome replication.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2018-09-16
    Kin Fan On,Matt Jaremko,Bruce Stillman,Leemor Joshua-Tor

    更新日期:2019-11-01
  • Understanding the 26S proteasome molecular machine from a structural and conformational dynamics perspective.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-30
    Eric R Greene,Ken C Dong,Andreas Martin

    The 26S proteasome is the essential compartmental protease in eukaryotic cells required for the ubiquitin-dependent clearance of damaged polypeptides and obsolete regulatory proteins. Recently, a combination of high-resolution structural, biochemical, and biophysical studies has provided crucial new insights into the mechanisms of this fascinating molecular machine. A multitude of new cryo-electron microscopy structures provided snapshots of the proteasome during ATP-hydrolysis-driven substrate translocation, and detailed biochemical studies revealed the timing of individual degradation steps, elucidating the mechanisms for substrate selection and the commitment to degradation through conformational transitions. It was uncovered how ubiquitin removal from substrates is mechanically coupled to degradation, and cryo-electron tomography studies gave a glimpse of active proteasomes inside the cell, their subcellular localization, and interactions with protein aggregates. Here, we summarize these advances in our mechanistic understanding of the proteasome, with a particular focus on how its structural features and conformational transitions enable the multi-step degradation process.

    更新日期:2019-11-01
  • Different mechanisms for translocation by monomeric and hexameric helicases.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-30
    Yang Gao,Wei Yang

    Helicases are ATP-dependent motor proteins that translocate along single-stranded or double-stranded nucleic acids to alter base-pairing structures or molecular interactions. Helicases can be divided to monomeric and hexameric types, each with distinct ternary structures, nucleic acid-binding modes, and translocation mechanisms. It is well established that monomeric helicases translocate by the inchworm mechanism. Recent structures of different superfamilies of hexameric helicases reveal that they use a hand-over hand mechanism for translocation. Structures of bacteriophage T7 replisome illustrate how helicase and polymerase cooperatively catalyze DNA unwinding. In this review, we survey structures of monomeric and hexameric helicases and compare different mechanisms for translocation.

    更新日期:2019-11-01
  • Advances in coarse-grained modeling of macromolecular complexes.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2018-12-07
    Alexander J Pak,Gregory A Voth

    Recent progress in coarse-grained (CG) molecular modeling and simulation has facilitated an influx of computational studies on biological macromolecules and their complexes. Given the large separation of length-scales and time-scales that dictate macromolecular biophysics, CG modeling and simulation are well-suited to bridge the microscopic and mesoscopic or macroscopic details observed from all-atom molecular simulations and experiments, respectively. In this review, we first summarize recent innovations in the development of CG models, which broadly include structure-based, knowledge-based, and dynamics-based approaches. We then discuss recent applications of different classes of CG models to explore various macromolecular complexes. Finally, we conclude with an outlook for the future in this ever-growing field of biomolecular modeling.

    更新日期:2019-11-01
  • Interpretation of medium resolution cryoEM maps of multi-protein complexes.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-07-31
    Ana Casañal,Shabih Shakeel,Lori A Passmore

    Electron cryo-microscopy (cryoEM) is used to determine structures of biological molecules, including multi-protein complexes. Maps at better than 3.0Å resolution are relatively straightforward to interpret since atomic models of proteins and nucleic acids can be built directly. Still, these resolutions are often difficult to achieve, and map quality frequently varies within a structure. This results in data that are challenging to interpret, especially when crystal structures or suitable homology models are not available. Recent advances in mass spectrometry techniques, computational methods and model building tools facilitate subunit/domain fitting into maps, elucidation of protein contacts, and de novo generation of atomic models. Here, we review techniques for map interpretation and provide examples from recent studies of multi-protein complexes.

    更新日期:2019-11-01
  • Tandem domain swapping: determinants of multidomain protein misfolding.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-07-02
    Aleix Lafita,Pengfei Tian,Robert B Best,Alex Bateman

    Tandem homologous domains in proteins are susceptible to misfolding through the formation of domain swaps, non-native conformations involving the exchange of equivalent structural elements between adjacent domains. Cutting-edge biophysical experiments have recently allowed the observation of tandem domain swapping events at the single molecule level. In addition, computer simulations have shed light into the molecular mechanisms of domain swap formation and serve as the basis for methods to systematically predict them. At present, the number of studies on tandem domain swaps is still small and limited to a few domain folds, but they offer important insights into the folding and evolution of multidomain proteins with applications in the field of protein design.

    更新日期:2019-11-01
  • Copper trafficking in eukaryotic systems: current knowledge from experimental and computational efforts.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-06-09
    Alessandra Magistrato,Matic Pavlin,Zena Qasem,Sharon Ruthstein

    Copper plays a vital role in fundamental cellular functions, and its concentration in the cell must be tightly regulated, as dysfunction of copper homeostasis is linked to severe neurological diseases and cancer. This review provides a compendium of current knowledge regarding the mechanism of copper transfer from the blood system to the Golgi apparatus; this mechanism involves the copper transporter hCtr1, the metallochaperone Atox1, and the ATPases ATP7A/B. We discuss key insights regarding the structural and functional properties of the hCtr1-Atox1-ATP7B cycle, obtained from diverse studies relying on distinct yet complementary biophysical, biochemical, and computational methods. We further address the mechanistic aspects of the cycle that continue to remain elusive. These knowledge gaps must be filled in order to be able to harness our understanding of copper transfer to develop therapeutic approaches with the capacity to modulate copper metabolism.

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Editorial overview: Macromolecular assemblies.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-08-14
    Ilya A Vakser,Andrzej Joachimiak

    更新日期:2019-11-01
  • Physical biology of GPCR signalling dynamics inferred from fluorescence spectroscopy and imaging.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-07-19
    Sergei Chavez-Abiega,Joachim Goedhart,Frank Johannes Bruggeman

    The physical biology of G protein-coupled receptor (GPCR) signalling can be inferred from imaging of single molecules and single living cells. In this opinion paper, we highlight recent developments in technologies to study GPCR signalling in vitro and in cyto. We start from mobility and localisation characteristics of single receptors in membranes. Subsequently, we discuss the kinetics of shifts in receptor-conformation equilibrium due to allosteric binding events and G protein activation. We continue with recent insights into downstream signalling and the role of delayed negative feedback to suppress GPCR signalling. Finally, we discuss new strategies to reveal how the multiplex signalling responses of cells to ligand mixtures, mediated by their entire receptor arsenal, can be disentangled, using single-cell data.

    更新日期:2019-11-01
  • Topology prediction of insect olfactory receptors.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-06-25
    Vikas Tiwari,Snehal D Karpe,Ramanathan Sowdhamini

    Olfactory receptors are important transmembrane proteins that enable organisms to perceive odours and react to them. Structural understanding of insect olfactory receptors is scarce. In this review, we discuss different transmembrane helix prediction methods, consensus methods, topology prediction methods which can enable topology prediction of these proteins. We discuss the current success rates by applying the algorithms on few G-protein coupled receptors of known structure and olfactory receptor sequences and outstanding challenges. Finally, we discuss the impact of topology prediction on biology and modeling of ORs.

    更新日期:2019-11-01
  • Telomerase structures and regulation: shedding light on the chromosome end.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-06-16
    Thi Hoang Duong Nguyen,Kathleen Collins,Eva Nogales

    During genome replication, telomerase adds repeats to the ends of chromosomes to balance the loss of telomeric DNA. The regulation of telomerase activity is of medical relevance, as it has been implicated in human diseases such as cancer, as well as in aging. Until recently, structural information on this enzyme that would facilitate its clinical manipulation had been lacking due to telomerase very low abundance in cells. Recent cryo-EM structures of both the human and Tetrahymena thermophila telomerases have provided a picture of both the shared catalytic core of telomerase and its interaction with species-specific factors that play different roles in telomerase RNP assembly and function. We discuss also progress toward an understanding of telomerase RNP biogenesis and telomere recruitment from recent studies.

    更新日期:2019-11-01
  • Structural bioinformatics analysis of variants on GPCR function.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-06-08
    Syed Askar Syed Haneef,Shoba Ranganathan

    G protein-coupled receptors (GPCRs) are key membrane-embedded receptor proteins, with critical roles in cellular signal transduction. In the era of precision medicine, understanding the role of natural variants on GPCR function is critical, especially from a pharmacogenomics viewpoint. Studies involved in mapping variants to GPCR structures are briefly reviewed here. The endocannabinoid system involving the central nervous system (CNS), the human cannabinoid receptor 1 (CB1), is an important drug target and its variability has implications for disease susceptibility and altered drug and pain response. We have carried out a computational study to map deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) to CB1. CB1 mutations were computationally evaluated from neutral to deleterious, and the top twelve deleterious mutations, with structural information, were found to be either close to the ligand binding region or the G-protein binding site. We have mapped these to the active and inactive CB1 X-ray crystallographic structures to correlate variants with available phenotypic information. We have also carried out molecular dynamics simulations to functionally characterize four selected mutants.

    更新日期:2019-11-01
  • Computational prediction of GPCR oligomerization.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-06-07
    Andrea Townsend-Nicholson,Nojood Altwaijry,Andrew Potterton,Inaki Morao,Alexander Heifetz

    There has been a recent and prolific expansion in the number of GPCR crystal structures being solved: in both active and inactive forms and in complex with ligand, with G protein and with each other. Despite this, there is relatively little experimental information about the precise configuration of GPCR oligomers during these different biologically relevant states. While it may be possible to identify the experimental conditions necessary to crystallize a GPCR preferentially in a specific structural conformation, computational approaches afford a potentially more tractable means of describing the probability of formation of receptor dimers and higher order oligomers. Ensemble-based computational methods based on structurally determined dimers, coupled with a computational workflow that uses quantum mechanical methods to analyze the chemical nature of the molecular interactions at a GPCR dimer interface, will generate the reproducible and accurate predictions needed to predict previously unidentified GPCR dimers and to inform future advances in our ability to understand and begin to precisely manipulate GPCR oligomers in biological systems. It may also provide information needed to achieve an increase in the number of experimentally determined oligomeric GPCR structures.

    更新日期:2019-11-01
  • Multicomponent assemblies in DNA-double-strand break repair by NHEJ.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-28
    Aleš Hnízda,Tom L Blundell

    Non-homologous end joining (NHEJ), a process for repair of DNA-breaks that does not require a DNA-template, involves synapsis, end-processing and ligation. Synapsis is initiated by assembly of the Ku-heterodimer on DNA broken ends, followed by the formation of DNA-dependent protein kinase (DNA-PK) - an assembly of the catalytic subunit (DNA-PKcs), the Ku-heterodimer and DNA. Recent progress in understanding the structural architecture of DNA-PK, achieved by X-ray crystallography and cryo-electron microscopy, has revealed a stage of DNA-PKcs on which other components from the pathway assemble and mediate kinase activity allosterically. This review provides a comparative overview of recently published structures of DNA-PK, together with a discussion of other complexes mediated by the Ku heterodimer. It also shows that some binders are specific to particular patho-physiological conditions.

    更新日期:2019-11-01
  • Large-scale simulations of nucleoprotein complexes: ribosomes, nucleosomes, chromatin, chromosomes and CRISPR.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-28
    Karissa Y Sanbonmatsu

    Recent advances in biotechnology such as Hi-C, CRISPR/Cas9 and ribosome display have placed nucleoprotein complexes at center stage. Understanding the structural dynamics of these complexes aids in optimizing protocols and interpreting data for these new technologies. The integration of simulation and experiment has helped advance mechanistic understanding of these systems. Coarse-grained simulations, reduced-description models, and explicit solvent molecular dynamics simulations yield useful complementary perspectives on nucleoprotein complex structural dynamics. When combined with Hi-C, cryo-EM, and single molecule measurements, these simulations integrate disparate forms of experimental data into a coherent mechanism.

    更新日期:2019-11-01
  • Importance of protein dynamics in the structure-based drug discovery of class A G protein-coupled receptors (GPCRs).
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-19
    Yoonji Lee,Raudah Lazim,Stephani Joy Y Macalino,Sun Choi

    Demand for novel GPCR modulators is increasing as the association between the GPCR signaling pathway and numerous diseases such as cancers, psychological and metabolic disorders continues to be established. In silico structure-based drug design (SBDD) offers an outlet where researchers could exploit the accumulating structural information of GPCR to expedite the process of drug discovery. The coupling of structure-based approaches such as virtual screening and molecular docking with molecular dynamics and/or Monte Carlo simulation aids in reflecting the dynamics of proteins in nature into previously static docking studies, thus enhancing the accuracy of rationally designed ligands. This review will highlight recent computational strategies that incorporate protein flexibility into SBDD of GPCR-targeted ligands.

    更新日期:2019-11-01
  • Charging the code - tRNA modification complexes.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-19
    Rościsław Krutyhołowa,Karol Zakrzewski,Sebastian Glatt

    All types of cellular RNAs are post-transcriptionally modified, constituting the so called 'epitranscriptome'. In particular, tRNAs and their anticodon stem loops represent major modification hotspots. The attachment of small chemical groups at the heart of the ribosomal decoding machinery can directly affect translational rates, reading frame maintenance, co-translational folding dynamics and overall proteome stability. The variety of tRNA modification patterns is driven by the activity of specialized tRNA modifiers and large modification complexes. Notably, the absence or dysfunction of these cellular machines is correlated with several human pathophysiologies. In this review, we aim to highlight the most recent scientific progress and summarize currently available structural information of the most prominent eukaryotic tRNA modifiers.

    更新日期:2019-11-01
  • Metadynamics simulations of ligand binding to GPCRs.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-18
    Passainte Ibrahim,Timothy Clark

    Recent developments in metadynamics simulation techniques for ligand binding to Class A GPCRs are described and the results obtained elucidated. The computational protocol makes good use of modern massively parallel hardware, making simulations of the binding/unbinding process routine. The simulations reveal unprecedented details of the ligand-binding pathways, including multiple binding sites in many cases. Free energies of binding are reproduced very well and the simulations allow prediction of the efficacy (agonist, antagonist etc.) of ligands.

    更新日期:2019-11-01
  • Allostery in G protein-coupled receptors investigated by molecular dynamics simulations.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-17
    João Marcelo Lamim Ribeiro,Marta Filizola

    G-protein-coupled receptors (GPCRs) are allosteric signaling machines that trigger distinct functional responses depending on the particular conformational state they adopt upon binding. This so-called GPCR functional selectivity is prompted by ligands of different efficacy binding at orthosteric or allosteric sites on the receptor, as well as by interactions with intracellular protein partners or other receptor types. Molecular dynamics (MD) simulations can provide important mechanistic, thermodynamic, and kinetic insights into these interactions at a level of molecular detail that is necessary to rightly inform modern drug discovery. Here, we review the most recent MD contributions to understanding GPCR allostery, with an emphasis on their strengths and limitations.

    更新日期:2019-11-01
  • Current status of multiscale simulations on GPCRs.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-15
    Serdar Durdagi,Berna Dogan,Ismail Erol,Gülru Kayık,Busecan Aksoydan

    Membrane receptors couple signaling pathways using various mechanisms. G Protein-Coupled Receptors (GPCRs) represent the largest class of membrane proteins involved in signal transduction across the biological membranes. They are essential targets for cell signaling and are of great commercial interest to the pharmaceutical industry. Recent advances made in molecular biology and computational chemistry offer a range of simulation and multiscale modeling tools for the definition and analysis of protein-ligand, protein-protein, and protein-membrane interactions. The development of new techniques on statistical methods and free energy simulations help to predict novel optimal ligands, G protein specificity and oligomerization. The identification of the ligand-binding activation mechanisms and atomistic determinants as well as the interactions of intracellular binding partners that bind to GPCR targets in different coupling states will provide greater safety in human life. In this review, recent approaches and applications of multiscale simulations on GPCRs were highlighted.

    更新日期:2019-11-01
  • Molecular switches in GPCRs.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-05-15
    Slawomir Filipek

    Molecular switches in GPCRs enable passing the signal from the agonist binding site, usually located close to the extracellular surface, to the intracellular part of the receptor. The switches are usually associated with conserved structural motifs on transmembrane helices (TMs), and they are accompanied by adjacent residues which provide the signal to the central residue in the toggle switch. In case of locks being the molecular switches, they are breaking (permanently or temporarily) upon agonist binding. Cascade action of switches is correlated with influx of water molecules to form a pathway linking both sides of the receptor. The switches remove the hydrophobic barriers and facilitate water movement while water molecules help to rearrange the hydrogen bond network inside the receptor.

    更新日期:2019-11-01
  • Characterising GPCR-ligand interactions using a fragment molecular orbital-based approach.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-04-26
    Alexander Heifetz,Tim James,Michelle Southey,Inaki Morao,Matteo Aldeghi,Laurie Sarrat,Dmitri G Fedorov,Mike J Bodkin,Andrea Townsend-Nicholson

    There has been fantastic progress in solving GPCR crystal structures. However, the ability of X-ray crystallography to guide the drug discovery process for GPCR targets is limited by the availability of accurate tools to explore receptor-ligand interactions. Visual inspection and molecular mechanics approaches cannot explain the full complexity of molecular interactions. Quantum mechanical approaches (QM) are often too computationally expensive, but the fragment molecular orbital (FMO) method offers an excellent solution that combines accuracy, speed and the ability to reveal key interactions that would otherwise be hard to detect. Integration of GPCR crystallography or homology modelling with FMO reveals atomistic details of the individual contributions of each residue and water molecule towards ligand binding, including an analysis of their chemical nature.

    更新日期:2019-11-01
  • High-symmetry protein assemblies: patterns and emerging applications.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-04-22
    Kevin A Cannon,Jessica M Ochoa,Todd O Yeates

    The accelerated elucidation of three-dimensional structures of protein complexes, both natural and designed, is providing new examples of large supramolecular assemblies with intriguing shapes. Those with high symmetry - based on the geometries of the Platonic solids - are particularly notable as their innately closed forms create interior spaces with varying degrees of enclosure. We survey known protein assemblies of this type and discuss their geometric features. The results bear on issues of protein function and evolution, while also guiding novel bioengineering applications. Recent successes using high-symmetry protein assemblies for applications in interior encapsulation and exterior display are highlighted.

    更新日期:2019-11-01
  • Applications of machine learning in GPCR bioactive ligand discovery.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-04-22
    Amara Jabeen,Shoba Ranganathan

    GPCRs constitute the largest druggable family having targets for 475 Food and Drug Administration (FDA) approved drugs. As GPCRs are of great interest to pharmaceutical industry, enormous efforts are being expended to find relevant and potent GPCR ligands as lead compounds. There are tens of millions of compounds present in different chemical databases. In order to scan this immense chemical space, computational methods, especially machine learning (ML) methods, are essential components of GPCR drug discovery pipelines. ML approaches have applications in both ligand-based and structure-based virtual screening. We present here a cheminformatics overview of ML applications to different stages of GPCR drug discovery. Focusing on olfactory receptors, which are the largest family of GPCRs, a case study for predicting agonists for an ectopic olfactory receptor, OR1G1, compares four classical ML methods.

    更新日期:2019-11-01
  • Computational approaches to macromolecular interactions in the cell.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-04-19
    Ilya A Vakser,Eric J Deeds

    Structural modeling of a cell is an evolving strategic direction in computational structural biology. It takes advantage of new powerful modeling techniques, deeper understanding of fundamental principles of molecular structure and assembly, and rapid growth of the amount of structural data generated by experimental techniques. Key modeling approaches to principal types of macromolecular assemblies in a cell already exist. The main challenge, along with the further development of these modeling approaches, is putting them together in a consistent, unified whole cell model. This opinion piece addresses the fundamental aspects of modeling macromolecular assemblies in a cell, and the state-of-the-art in modeling of the principal types of such assemblies.

    更新日期:2019-11-01
  • The ATP-powered gymnastics of TRiC/CCT: an asymmetric protein folding machine with a symmetric origin story.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-04-13
    Daniel Gestaut,Antonio Limatola,Lukasz Joachimiak,Judith Frydman

    The eukaryotic chaperonin TRiC/CCT is a large hetero-oligomeric complex that plays an essential role assisting cellular protein folding and suppressing protein aggregation. It consists of two rings, and each composed of eight different subunits; non-native polypeptides bind and fold in an ATP-dependent manner within their central chamber. Here, we review recent advances in our understanding of TRiC structure and mechanism enabled by application of hybrid structural methods including the integration of cryo-electron microscopy with distance constraints from crosslinking mass spectrometry. These new insights are revealing how the different TRiC/CCT subunits create asymmetry in its ATP-driven conformational cycle and its interaction with non-native polypeptides, which ultimately underlie its unique ability to fold proteins that cannot be folded by other chaperones.

    更新日期:2019-11-01
  • Principles and characteristics of biological assemblies in experimentally determined protein structures.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-04-10
    Qifang Xu,Roland L Dunbrack

    More than half of all structures in the PDB are assemblies of two or more proteins, including both homooligomers and heterooligomers. Structural information on these assemblies comes from X-ray crystallography, NMR, and cryo-EM spectroscopy. The correct assembly in an X-ray structure is often ambiguous, and computational methods have been developed to identify the most likely biologically relevant assembly based on physical properties of assemblies and sequence conservation in interfaces. Taking advantage of the large number of structures now available, some of the most recent methods have relied on similarity of interfaces and assemblies across structures of homologous proteins.

    更新日期:2019-11-01
  • Multiscale simulations on human Frizzled and Taste2 GPCRs.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-04-02
    Mercedes Alfonso-Prieto,Alejandro Giorgetti,Paolo Carloni

    Recently, molecular dynamics simulations, from all atom and coarse grained to hybrid methods bridging the two scales, have provided exciting functional insights into class F (Frizzled and Taste2) GPCRs (about 40 members in humans). Findings include: (i) The activation of one member of the Frizzled receptors (FZD4) involves a bending of transmembrane helix TM7 far larger than that in class A GPCRs. (ii) The affinity of an anticancer drug targeting another member (Smoothened receptor) decreases in a specific drug-resistant variant, because the mutation ultimately disrupts the binding cavity and affects TM6. (iii) A novel two-state recognition mechanism explains the very large agonist diversity for at least one member of the Taste2 GPCRs, hTAS2R46.

    更新日期:2019-11-01
  • Computational design for thermostabilization of GPCRs.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-03-26
    Petr Popov,Igor Kozlovskii,Vsevolod Katritch

    GPCR superfamily is the largest clinically relevant family of targets in human genome; however, low thermostability and high conformational plasticity of these integral membrane proteins make them notoriously hard to handle in biochemical, biophysical, and structural experiments. Here, we describe the recent advances in computational approaches to design stabilizing mutations for GPCR that take advantage of the structural and sequence conservation properties of the receptors, and employ machine learning on accumulated mutation data for the superfamily. The fast and effective computational tools can provide a viable alternative to existing experimental mutation screening and are poised for further improvements with expansion of thermostability datasets for training the machine learning models. The rapidly growing practical applications of computational stability design streamline GPCR structure determination and may contribute to more efficient drug discovery.

    更新日期:2019-11-01
  • Automated discovery of GPCR bioactive ligands.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-03-26
    Sebastian Raschka

    While G-protein-coupled receptors (GPCRs) constitute the largest class of membrane proteins, structures and endogenous ligands of a large portion of GPCRs remain unknown. Because of the involvement of GPCRs in various signaling pathways and physiological roles, the identification of endogenous ligands as well as designing novel drugs is of high interest to the research and medical communities. Along with highlighting the recent advances in structure-based ligand discovery, including docking and molecular dynamics, this article focuses on the latest advances for automating the discovery of bioactive ligands using machine learning. Machine learning is centered around the development and applications of algorithms that can learn from data automatically. Such an approach offers immense opportunities for bioactivity prediction as well as quantitative structure-activity relationship studies. This review describes the most recent and successful applications of machine learning for bioactive ligand discovery, concluding with an outlook on deep learning methods that are capable of automatically extracting salient information from structural data as a promising future direction for rapid and efficient bioactive ligand discovery.

    更新日期:2019-11-01
  • What method to use for protein-protein docking?
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-02-04
    Kathryn A Porter,Israel Desta,Dima Kozakov,Sandor Vajda

    A number of well-established servers perform 'free' docking of proteins of known structures. In contrast, template-based docking can start from sequences if structures are available for complexes that are homologous to the target. On the basis of the results of the CAPRI-CASP structure prediction experiments, template-based methods yield more accurate predictions if good templates can be found, but generally fail without such templates. However, free global docking, or focused docking around even poor quality template-based models, can still generate acceptable docked structures in these cases. In accordance with the analysis of a benchmark set, free docking of heterodimers yields acceptable or better predictions in the top 10 models for around 40% of structures. However, it is likely that a combination of template-based and free docking methods can perform better for targets that have template structures available. Another way of improving the reliability of predictions is adding experimental information as restraints, an option built into several docking servers.

    更新日期:2019-11-01
  • Regulatory mechanisms in postsynaptic phosphorylation networks.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-02-27
    Marcelo P Coba

    The modulation of the postsynaptic signaling machinery by protein phosphorylation has attracted much interest since it is key for the understanding of the regulation of a variety of synaptic functions. While advances in mass spectrometry have allowed us to begin performing large-scale analysis of protein phosphorylation in components of the PSD, the systematic collection of datasets and their functional significance within the context of regulatory signaling networks is in its infancy. Here, we will focus on the composition of the PSD phosphoproteome describing kinase, phosphatase, and protein domain modules involved in the regulation of phosphorylation signaling. We will discuss the impact of synaptic plasticity mechanisms such as long-term potentiation (LTP) in mammalian kinomes and describe the general rules of signaling organization in the PSD phosphoproteome.

    更新日期:2019-11-01
  • Amyloid structures: much more than just a cross-β fold.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-11-05
    Rodrigo Gallardo,Neil A Ranson,Sheena E Radford

    In recent years our understanding of amyloid structure has been revolutionised by innovations in cryo-electron microscopy, electron diffraction and solid-state NMR. These techniques have yielded high-resolution structures of fibrils isolated from patients with neurodegenerative disease, as well as those formed from amyloidogenic proteins in vitro. The results not only show the expected cross-β amyloid structure, but also reveal that the amyloid fold is unexpectedly diverse and complex. Here, we discuss this diversity, highlighting dynamic regions, ligand binding motifs, cavities, non-protein components, and structural polymorphism. Collectively, these variations combine to allow the generic amyloid fold to be realised in three dimensions in different ways, and this diversity may be related to the roles of fibrils in disease.

    更新日期:2019-11-01
  • Intrinsic protein disorder and protein modifications in the processing of biological signals.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-10-20
    Aaron H Phillips,Richard W Kriwacki

    Eukaryotic cells are highly complex systems; however, they manage to attain this complexity with a surprisingly small number of protein products. This is due, in part, to the fact that the functions of the eukaryotic proteome can be modulated and controlled by a vast network of largely reversible post-translational modifications. Such modifications change the chemical nature of certain amino acid side chains and thereby can be used to modulate diverse protein functions such as enzyme activity and binding events. Here we review recent advances in the characterization of the native mechanisms by which cells utilize post-translational modifications to send biological signals as well as recent successes in engineering such systems. We highlight roles for protein disorder in signal propagation in these systems.

    更新日期:2019-11-01
  • Structural biology of glutamate receptor ion channels: towards an understanding of mechanism.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2019-06-12
    Ingo H Greger,Mark L Mayer

    Ionotropic glutamate receptors (iGluRs) are tetrameric ion channels that mediate signal transmission at neuronal synapses, where they contribute centrally to the postsynaptic plasticity that underlies learning and memory. Receptor activation by l-glutamate triggers complex allosteric cascades that are transmitted through the layered and highly flexible receptor assembly culminating in opening a cation-selective pore. This process is shaped by the arrangement of the four core subunits as well as the presence of various auxiliary subunits, and is subject to regulation by an array of small molecule modulators targeting a number of sites throughout the complex. Here, we discuss recent structures of iGluR homomers and heteromers illuminating the organization and subunit arrangement of the core tetramer, co-assembled with auxiliary subunits and in complex with allosteric modulators.

    更新日期:2019-11-01
  • Clarity through structures. Editorial overview.
    Curr. Opin. Struc. Biol. (IF 7.052) Pub Date : 2000-12-15
    Stubbe,Johnson

    更新日期:2019-11-01
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