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  • Prospecting for molecular glues
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-08-03
    Willem den Besten; J. Russell Lipford

    Two recent studies identified CDK12 inhibitors that bind to CDK12–cyclin K complexes and act as molecular glues to stabilize an interaction with the ubiquitin ligase CUL4–DDB1, leading to cyclin K degradation.

    更新日期:2020-08-03
  • Rational discovery of molecular glue degraders via scalable chemical profiling
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-08-03
    Cristina Mayor-Ruiz; Sophie Bauer; Matthias Brand; Zuzanna Kozicka; Marton Siklos; Hana Imrichova; Ines H. Kaltheuner; Elisa Hahn; Kristina Seiler; Anna Koren; Georg Petzold; Michaela Fellner; Christoph Bock; André C. Müller; Johannes Zuber; Matthias Geyer; Nicolas H. Thomä; Stefan Kubicek; Georg E. Winter

    Targeted protein degradation is a new therapeutic modality based on drugs that destabilize proteins by inducing their proximity to E3 ubiquitin ligases. Of particular interest are molecular glues that can degrade otherwise unligandable proteins by orchestrating direct interactions between target and ligase. However, their discovery has so far been serendipitous, thus hampering broad translational efforts

    更新日期:2020-08-03
  • Bariatric surgery reveals a gut-restricted TGR5 agonist with anti-diabetic effects
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-08-03
    Snehal N. Chaudhari; David A. Harris; Hassan Aliakbarian; James N. Luo; Matthew T. Henke; Renuka Subramaniam; Ashley H. Vernon; Ali Tavakkoli; Eric G. Sheu; A. Sloan Devlin

    Bariatric surgery, the most effective treatment for obesity and type 2 diabetes, is associated with increased levels of the incretin hormone glucagon-like peptide-1 (GLP-1) and changes in levels of circulating bile acids. The levels of individual bile acids in the gastrointestinal (GI) tract after surgery have, however, remained largely unstudied. Using ultra-high performance liquid chromatography–mass

    更新日期:2020-08-03
  • Structural basis for RING-Cys-Relay E3 ligase activity and its role in axon integrity
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-08-03
    Peter D. Mabbitt; Andrea Loreto; Marc-André Déry; Adam J. Fletcher; Mathew Stanley; Kuan-Chuan Pao; Nicola T. Wood; Michael P. Coleman; Satpal Virdee

    MYCBP2 is a ubiquitin (Ub) E3 ligase (E3) that is essential for neurodevelopment and regulates axon maintenance. MYCBP2 transfers Ub to nonlysine substrates via a newly discovered RING-Cys-Relay (RCR) mechanism, where Ub is relayed from an upstream cysteine to a downstream substrate esterification site. The molecular bases for E2–E3 Ub transfer and Ub relay are unknown. Whether these activities are

    更新日期:2020-08-03
  • Engineering orthogonal human O- linked glycoprotein biosynthesis in bacteria
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-27
    Aravind Natarajan; Thapakorn Jaroentomeechai; Marielisa Cabrera-Sánchez; Jody C. Mohammed; Emily C. Cox; Olivia Young; Asif Shajahan; Michael Vilkhovoy; Sandra Vadhin; Jeffrey D. Varner; Parastoo Azadi; Matthew P. DeLisa

    A major objective of synthetic glycobiology is to re-engineer existing cellular glycosylation pathways from the top down or construct non-natural ones from the bottom up for new and useful purposes. Here, we have developed a set of orthogonal pathways for eukaryotic O-linked protein glycosylation in Escherichia coli that installed the cancer-associated mucin-type glycans Tn, T, sialyl-Tn and sialyl-T

    更新日期:2020-07-27
  • p63 uses a switch-like mechanism to set the threshold for induction of apoptosis
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-27
    Jakob Gebel; Marcel Tuppi; Apirat Chaikuad; Katharina Hötte; Martin Schröder; Laura Schulz; Frank Löhr; Niklas Gutfreund; Franziska Finke; Erik Henrich; Julija Mezhyrova; Ralf Lehnert; Francesco Pampaloni; Gerhard Hummer; Ernst H. K. Stelzer; Stefan Knapp; Volker Dötsch

    The p53 homolog TAp63α is the transcriptional key regulator of genome integrity in oocytes. After DNA damage, TAp63α is activated by multistep phosphorylation involving multiple phosphorylation events by the kinase CK1, which triggers the transition from a dimeric and inactive conformation to an open and active tetramer that initiates apoptosis. By measuring activation kinetics in ovaries and single-site

    更新日期:2020-07-27
  • Enzymatic C–H activation of aromatic compounds through CO 2 fixation
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-27
    Godwin A. Aleku; Annica Saaret; Ruth T. Bradshaw-Allen; Sasha R. Derrington; Gabriel R. Titchiner; Irina Gostimskaya; Deepankar Gahloth; David A. Parker; Sam Hay; David Leys

    The direct C–H carboxylation of aromatic compounds is an attractive route to the corresponding carboxylic acids, but remains challenging under mild conditions. It has been proposed that the first step in anaerobic microbial degradation of recalcitrant aromatic compounds is a UbiD-mediated carboxylation. In this study, we use the UbiD enzyme ferulic acid decarboxylase (Fdc) in combination with a carboxylic

    更新日期:2020-07-27
  • NADP modulates RNA m 6 A methylation and adipogenesis via enhancing FTO activity
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-27
    Lina Wang; Chengli Song; Na Wang; Songyu Li; Qiaoling Liu; Zhen Sun; Kai Wang; Shi-Cang Yu; Qingkai Yang

    Metabolism is often regulated by the transcription and translation of RNA. In turn, it is likely that some metabolites regulate enzymes controlling reversible RNA modification, such as N6-methyladenosine (m6A), to modulate RNA. This hypothesis is at least partially supported by the findings that multiple metabolic diseases are highly associated with fat mass and obesity-associated protein (FTO), an

    更新日期:2020-07-27
  • Living cells as test tubes
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-24
    Roshan Mammen Regy; Jeetain Mittal

    Thermodynamic principles are used to map the phase behavior of a tunable protein-binding system under crowded cellular conditions. This study marks a substantial step forward in relating molecular interactions to material properties and cellular processes involving protein self-assembly.

    更新日期:2020-07-24
  • Publisher Correction: Acoustic biosensors for ultrasound imaging of enzyme activity
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-23
    Anupama Lakshmanan; Zhiyang Jin; Suchita P. Nety; Daniel P. Sawyer; Audrey Lee-Gosselin; Dina Malounda; Mararet B. Swift; David Maresca; Mikhail G. Shapiro

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-07-23
  • A stress-free stress response
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-23
    Nadia Cummins; Rebecca C. Taylor

    A new molecule that specifically activates a key protein homeostasis pathway has been identified. The ability to initiate the IRE1–XBP1s branch of the unfolded protein response opens up new avenues for basic research and treatment of disease.

    更新日期:2020-07-23
  • Author Correction: Optogenetic control of cofilin and αTAT in living cells using Z-lock
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-21
    Orrin J. Stone; Neha Pankow; Bei Liu; Ved P. Sharma; Robert J. Eddy; Hui Wang; Andrew T. Putz; Frank D. Teets; Brian Kuhlman; John S. Condeelis; Klaus M. Hahn

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-07-21
  • Decoding GEFs of animated cells
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-21
    Dean E. Natwick; Sean R. Collins

    Rho family GTPases regulate cell behaviors through complex signaling networks that act on rapid timescales in subcellular spatial domains. New live-cell biosensors and analytical methods now provide critical tools to dissect Rho GTPase regulation and to better understand cellular information processing.

    更新日期:2020-07-21
  • Chemical strategies to overcome resistance against targeted anticancer therapeutics
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-21
    Rudolf Pisa; Tarun M. Kapoor

    Emergence of resistance is a major factor limiting the efficacy of molecularly targeted anticancer drugs. Understanding the specific mutations, or other genetic or cellular changes, that confer drug resistance can help in the development of therapeutic strategies with improved efficacies. Here, we outline recent progress in understanding chemotype-specific mechanisms of resistance and present chemical

    更新日期:2020-07-21
  • A mass spectrometry-based proteome map of drug action in lung cancer cell lines
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-20
    Benjamin Ruprecht; Julie Di Bernardo; Zhao Wang; Xuan Mo; Oleg Ursu; Matthew Christopher; Rafael B. Fernandez; Li Zheng; Brian D. Dill; Huijun Wang; Yuting Xu; Andy Liaw; Jonathan D. Mortison; Nirodhini Siriwardana; Brian Andresen; Meir Glick; James R. Tata; Victoria Kutilek; Ivan Cornella-Taracido; An Chi

    Mass spectrometry-based discovery proteomics is an essential tool for the proximal readout of cellular drug action. Here, we apply a robust proteomic workflow to rapidly profile the proteomes of five lung cancer cell lines in response to more than 50 drugs. Integration of millions of quantitative protein–drug associations substantially improved the mechanism of action (MoA) deconvolution of single

    更新日期:2020-07-20
  • Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-20
    Julia M. D. Grandjean; Aparajita Madhavan; Lauren Cech; Bryan O. Seguinot; Ryan J. Paxman; Emery Smith; Louis Scampavia; Evan T. Powers; Christina B. Cooley; Lars Plate; Timothy P. Spicer; Jeffery W. Kelly; R. Luke Wiseman

    Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening

    更新日期:2020-07-20
  • Development of a chemical probe against NUDT15
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-20
    Si Min Zhang; Matthieu Desroses; Anna Hagenkort; Nicholas C. K. Valerie; Daniel Rehling; Megan Carter; Olov Wallner; Tobias Koolmeister; Adam Throup; Ann-Sofie Jemth; Ingrid Almlöf; Olga Loseva; Thomas Lundbäck; Hanna Axelsson; Shruti Regmi; Antonio Sarno; Andreas Krämer; Linda Pudelko; Lars Bräutigam; Azita Rasti; Mona Göttmann; Elisée Wiita; Juliane Kutzner; Torsten Schaller; Christina Kalderén;

    The NUDIX hydrolase NUDT15 was originally implicated in sanitizing oxidized nucleotides, but was later shown to hydrolyze the active thiopurine metabolites, 6-thio-(d)GTP, thereby dictating the clinical response of this standard-of-care treatment for leukemia and inflammatory diseases. Nonetheless, its physiological roles remain elusive. Here, we sought to develop small-molecule NUDT15 inhibitors to

    更新日期:2020-07-20
  • Structural insights into probe-dependent positive allosterism of the GLP-1 receptor
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-20
    Ana B. Bueno; Bingfa Sun; Francis S. Willard; Dan Feng; Joseph D. Ho; David B. Wainscott; Aaron D. Showalter; Michal Vieth; Qi Chen; Cynthia Stutsman; Betty Chau; James Ficorilli; Francisco J. Agejas; Graham R. Cumming; Alma Jiménez; Isabel Rojo; Tong Sun Kobilka; Brian K. Kobilka; Kyle W. Sloop

    Drugs that promote the association of protein complexes are an emerging therapeutic strategy. We report discovery of a G protein-coupled receptor (GPCR) ligand that stabilizes an active state conformation by cooperatively binding both the receptor and orthosteric ligand, thereby acting as a ‘molecular glue’. LSN3160440 is a positive allosteric modulator of the GLP-1R optimized to increase the affinity

    更新日期:2020-07-20
  • Multiplexed genomic encoding of non-canonical amino acids for labeling large complexes
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-20
    Bijoy J. Desai; Ruben L. Gonzalez

    Stunning advances in the structural biology of multicomponent biomolecular complexes (MBCs) have ushered in an era of intense, structure-guided mechanistic and functional studies of these complexes. Nonetheless, existing methods to site-specifically conjugate MBCs with biochemical and biophysical labels are notoriously impracticable and/or significantly perturb MBC assembly and function. To overcome

    更新日期:2020-07-20
  • Author Correction: The bottromycin epimerase BotH defines a group of atypical α/β-hydrolase-fold enzymes
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-15
    Asfandyar Sikandar; Laura Franz; Sebastian Adam; Javier Santos-Aberturas; Liliya Horbal; Andriy Luzhetskyy; Andrew W. Truman; Olga V. Kalinina; Jesko Koehnke

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-07-15
  • Expanding the membrane-protein NMR toolkit
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-14
    Ricky C. Cheng; Merritt Maduke

    An NMR method to monitor conformational states of challenging large protein targets is described. The method, which can be used to evaluate distances between two labels and to measure conformational exchange rates, revealed an unanticipated outward-facing state in a glutamate transporter.

    更新日期:2020-07-14
  • A quantitative method for proteome reallocation using minimal regulatory interventions
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-13
    Gustavo Lastiri-Pancardo; Jonathan S. Mercado-Hernández; Juhyun Kim; José I. Jiménez; José Utrilla

    Engineering resource allocation in biological systems is an ongoing challenge. Organisms allocate resources for ensuring survival, reducing the productivity of synthetic biology functions. Here we present a new approach for engineering the resource allocation of Escherichia coli by rationally modifying its transcriptional regulatory network. Our method (ReProMin) identifies the minimal set of genetic

    更新日期:2020-07-13
  • Acoustic biosensors for ultrasound imaging of enzyme activity
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-13
    Anupama Lakshmanan; Zhiyang Jin; Suchita P. Nety; Daniel P. Sawyer; Audrey Lee-Gosselin; Dina Malounda; Mararet B. Swift; David Maresca; Mikhail G. Shapiro

    Visualizing biomolecular and cellular processes inside intact living organisms is a major goal of chemical biology. However, existing molecular biosensors, based primarily on fluorescent emission, have limited utility in this context due to the scattering of light by tissue. In contrast, ultrasound can easily image deep tissue with high spatiotemporal resolution, but lacks the biosensors needed to

    更新日期:2020-07-13
  • Designer protein assemblies with tunable phase diagrams in living cells
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-13
    Meta Heidenreich; Joseph M. Georgeson; Emanuele Locatelli; Lorenzo Rovigatti; Saroj Kumar Nandi; Avital Steinberg; Yotam Nadav; Eyal Shimoni; Samuel A. Safran; Jonathan P. K. Doye; Emmanuel D. Levy

    Protein self-organization is a hallmark of biological systems. Although the physicochemical principles governing protein–protein interactions have long been known, the principles by which such nanoscale interactions generate diverse phenotypes of mesoscale assemblies, including phase-separated compartments, remain challenging to characterize. To illuminate such principles, we create a system of two

    更新日期:2020-07-13
  • Allosteric interactions in the parathyroid hormone GPCR–arrestin complex formation
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-06
    Lisa J. Clark; James Krieger; Alex D. White; Vasyl Bondarenko; Saifei Lei; Fei Fang; Ji Young Lee; Pemra Doruker; Thore Böttke; Frederic Jean-Alphonse; Pei Tang; Thomas J. Gardella; Kunhong Xiao; Ieva Sutkeviciute; Irene Coin; Ivet Bahar; Jean-Pierre Vilardaga

    Peptide ligands of class B G-protein-coupled receptors act via a two-step binding process, but the essential mechanisms that link their extracellular binding to intracellular receptor–arrestin interactions are not fully understood. Using NMR, crosslinking coupled to mass spectrometry, signaling experiments and computational approaches on the parathyroid hormone (PTH) type 1 receptor (PTHR), we show

    更新日期:2020-07-06
  • Architecture and functional dynamics of the pentafunctional AROM complex
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-06
    Harshul Arora Verasztó; Maria Logotheti; Reinhard Albrecht; Alexander Leitner; Hongbo Zhu; Marcus D. Hartmann

    The AROM complex is a multifunctional metabolic machine with ten enzymatic domains catalyzing the five central steps of the shikimate pathway in fungi and protists. We determined its crystal structure and catalytic behavior, and elucidated its conformational space using a combination of experimental and computational approaches. We derived this space in an elementary approach, exploiting an abundance

    更新日期:2020-07-06
  • Formation and functionalization of membraneless compartments in Escherichia coli
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-29
    Shao-Peng Wei; Zhi-Gang Qian; Chun-Fei Hu; Fang Pan; Meng-Ting Chen; Sang Yup Lee; Xiao-Xia Xia

    Membraneless organelles formed by liquid–liquid phase separation of proteins or nucleic acids are involved in diverse biological processes in eukaryotes. However, such cellular compartments have yet to be discovered or created synthetically in prokaryotes. Here, we report the formation of liquid protein condensates inside the cells of prokaryotic Escherichia coli upon heterologous overexpression of

    更新日期:2020-06-29
  • Tetracenomycin X inhibits translation by binding within the ribosomal exit tunnel
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-29
    Ilya A. Osterman; Maximiliane Wieland; Tinashe P. Maviza; Kseniya A. Lashkevich; Dmitrii A. Lukianov; Ekaterina S. Komarova; Yuliya V. Zakalyukina; Robert Buschauer; Dmitrii I. Shiriaev; Semen A. Leyn; Jaime E. Zlamal; Mikhail V. Biryukov; Dmitry A. Skvortsov; Vadim N. Tashlitsky; Vladimir I. Polshakov; Jingdong Cheng; Yury S. Polikanov; Alexey A. Bogdanov; Andrei L. Osterman; Sergey E. Dmitriev; Roland

    The increase in multi-drug resistant pathogenic bacteria is making our current arsenal of clinically used antibiotics obsolete, highlighting the urgent need for new lead compounds with distinct target binding sites to avoid cross-resistance. Here we report that the aromatic polyketide antibiotic tetracenomycin (TcmX) is a potent inhibitor of protein synthesis, and does not induce DNA damage as previously

    更新日期:2020-06-29
  • The bottromycin epimerase BotH defines a group of atypical α/β-hydrolase-fold enzymes
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-29
    Asfandyar Sikandar; Laura Franz; Sebastian Adam; Javier Santos-Aberturas; Liliya Horbal; Andriy Luzhetskyy; Andrew W. Truman; Olga V. Kalinina; Jesko Koehnke

    d-amino acids endow peptides with diverse, desirable properties, but the post-translational and site-specific epimerization of l-amino acids into their d-counterparts is rare and chemically challenging. Bottromycins are ribosomally synthesized and post-translationally modified peptides that have overcome this challenge and feature a d-aspartate (d-Asp), which was proposed to arise spontaneously during

    更新日期:2020-06-29
  • Publisher Correction: Structural insights into β-1,3-glucan cleavage by a glycoside hydrolase family
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-25
    Camila R. Santos; Pedro A. C. R. Costa; Plínio S. Vieira; Sinkler E. T. Gonzalez; Thamy L. R. Correa; Evandro A. Lima; Fernanda Mandelli; Renan A. S. Pirolla; Mariane N. Domingues; Lucelia Cabral; Marcele P. Martins; Rosa L. Cordeiro; Atílio T. Junior; Beatriz P. Souza; Érica T. Prates; Fabio C. Gozzo; Gabriela F. Persinoti; Munir S. Skaf; Mario T. Murakami

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-06-25
  • Better editors.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-01
    Yiyun Song

    更新日期:2020-06-24
  • Taking out the trash.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-01
    Grant Miura

    更新日期:2020-06-24
  • Passing the acid test.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-01
    Caitlin Deane

    更新日期:2020-06-24
  • Groovy RNA polymerase.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-07-01
    Mirella Bucci

    更新日期:2020-06-24
  • Discovering Nature's super glue.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-22
    Zhi Zeng,Ting Han

    Molecular glues induce novel protein–protein interactions to modulate protein function and downstream biology. A recent study unveils manumycin polyketides with multiple electrophilic centers as covalent molecular glues between UBR7 and TP53.

    更新日期:2020-06-23
  • Manumycin polyketides act as molecular glues between UBR7 and P53.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-22
    Yosuke Isobe,Mikiko Okumura,Lynn M McGregor,Scott M Brittain,Michael D Jones,Xiaoyou Liang,Ross White,William Forrester,Jeffrey M McKenna,John A Tallarico,Markus Schirle,Thomas J Maimone,Daniel K Nomura

    Molecular glues are an intriguing therapeutic modality that harness small molecules to induce interactions between proteins that typically do not interact. However, such molecules are rare and have been discovered fortuitously, thus limiting their potential as a general strategy for therapeutic intervention. We postulated that natural products bearing one or more electrophilic sites may be an unexplored

    更新日期:2020-06-23
  • 5-LOX inhibition by natural products.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-22
    Homero Rubbo,Irene Wood

    The enzyme 5-lipoxygenase (5-LOX) initiates the biosynthesis of leukotrienes (LT), potent mediators of the inflammatory response. The first crystal structures of two complexes of inhibitor bound to 5-LOX reveal the functional consequences of the binding, including a change in the regiospecificity toward a 12/15-lipoxygenating enzyme.

    更新日期:2020-06-23
  • The uninhibited pathway is not worth studying.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-22
    Michael E Pacold

    Glucose 6-phosphate dehydrogenase (G6PD) stands at the head of the pentose phosphate pathway, which is responsible for nucleotide synthesis. The identification and thorough validation of an improved G6PD inhibitor provide a valuable new tool compound for studying metabolism.

    更新日期:2020-06-23
  • Spectroscopic coherent Raman imaging of Caenorhabditis elegans reveals lipid particle diversity.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-22
    Wei-Wen Chen,George A Lemieux,Charles H Camp,Ta-Chau Chang,Kaveh Ashrafi,Marcus T Cicerone

    Caenorhabditis elegans serves as a model for understanding adiposity and its connections to aging. Current methodologies do not distinguish between fats serving the energy needs of the parent, akin to mammalian adiposity, from those that are distributed to the progeny, making it difficult to accurately interpret the physiological implications of fat content changes induced by external perturbations

    更新日期:2020-06-23
  • Structural insight into the formation of lipoprotein-β-barrel complexes.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-22
    Raquel Rodríguez-Alonso,Juliette Létoquart,Van Son Nguyen,Gwennaelle Louis,Antonio N Calabrese,Bogdan I Iorga,Sheena E Radford,Seung-Hyun Cho,Han Remaut,Jean-François Collet

    The β-barrel assembly machinery (BAM) inserts outer membrane β-barrel proteins (OMPs) in the outer membrane of Gram-negative bacteria. In Enterobacteriacea, BAM also mediates export of the stress sensor lipoprotein RcsF to the cell surface by assembling RcsF–OMP complexes. Here, we report the crystal structure of the key BAM component BamA in complex with RcsF. BamA adopts an inward-open conformation

    更新日期:2020-06-23
  • Dissecting the Pol II transcription cycle and derailing cancer with CDK inhibitors.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-22
    Pabitra K Parua,Robert P Fisher

    Largely non-overlapping sets of cyclin-dependent kinases (CDKs) regulate cell division and RNA polymerase II (Pol II)-dependent transcription. Here we review the molecular mechanisms by which specific CDKs are thought to act at discrete steps in the transcription cycle and describe the recent emergence of transcriptional CDKs as promising drug targets in cancer. We emphasize recent advances in understanding

    更新日期:2020-06-23
  • Enzymes knuckle down to the job.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-17
    Paul H Walton

    A suite of new enzymes reveals more on how Nature breaks down plant-based polysaccharides and how these enzymes might be harnessed in the utilization of plant-based biomass.

    更新日期:2020-06-17
  • Unraveling proteasome engagement.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-15
    Cameron G Roberts,Jonathan N Pruneda

    A new study reveals that, in addition to its longstanding role in recruiting proteins to the proteasome, ubiquitination can also induce a structural destabilization that allows the target protein to be efficiently unraveled for degradation.

    更新日期:2020-06-15
  • In vitro prototyping and rapid optimization of biosynthetic enzymes for cell design.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-15
    Ashty S Karim,Quentin M Dudley,Alex Juminaga,Yongbo Yuan,Samantha A Crowe,Jacob T Heggestad,Shivani Garg,Tanus Abdalla,William S Grubbe,Blake J Rasor,David N Coar,Maria Torculas,Michael Krein,FungMin Eric Liew,Amy Quattlebaum,Rasmus O Jensen,Jeffrey A Stuart,Sean D Simpson,Michael Köpke,Michael C Jewett

    The design and optimization of biosynthetic pathways for industrially relevant, non-model organisms is challenging due to transformation idiosyncrasies, reduced numbers of validated genetic parts and a lack of high-throughput workflows. Here we describe a platform for in vitro prototyping and rapid optimization of biosynthetic enzymes (iPROBE) to accelerate this process. In iPROBE, cell lysates are

    更新日期:2020-06-15
  • Single-molecule analysis reveals agonist-specific dimer formation of µ-opioid receptors.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-15
    Jan Möller,Ali Isbilir,Titiwat Sungkaworn,Brendan Osberg,Christos Karathanasis,Vikram Sunkara,Eugene O Grushevskyi,Andreas Bock,Paolo Annibale,Mike Heilemann,Christof Schütte,Martin J Lohse

    G-protein-coupled receptors (GPCRs) are key signaling proteins that mostly function as monomers, but for several receptors constitutive dimer formation has been described and in some cases is essential for function. Using single-molecule microscopy combined with super-resolution techniques on intact cells, we describe here a dynamic monomer–dimer equilibrium of µ-opioid receptors (µORs), where dimer

    更新日期:2020-06-15
  • Author Correction: Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-12
    Gloria Yang,Dave W Anderson,Florian Baier,Elias Dohmen,Nansook Hong,Paul D Carr,Shina Caroline Lynn Kamerlin,Colin J Jackson,Erich Bornberg-Bauer,Nobuhiko Tokuriki

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-06-12
  • Use of paramagnetic 19F NMR to monitor domain movement in a glutamate transporter homolog.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-08
    Yun Huang,Xiaoyu Wang,Guohua Lv,Asghar M Razavi,Gerard H M Huysmans,Harel Weinstein,Clay Bracken,David Eliezer,Olga Boudker

    In proteins where conformational changes are functionally important, the number of accessible states and their dynamics are often difficult to establish. Here we describe a novel 19F-NMR spectroscopy approach to probe dynamics of large membrane proteins. We labeled a glutamate transporter homolog with a 19F probe via cysteine chemistry and with a Ni2+ ion via chelation by a di-histidine motif. We used

    更新日期:2020-06-08
  • Discovery of small-molecule enzyme activators by activity-based protein profiling.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-08
    Bernard P Kok,Srijana Ghimire,Woojoo Kim,Shreyosree Chatterjee,Tyler Johns,Seiya Kitamura,Jerome Eberhardt,Daisuke Ogasawara,Janice Xu,Ara Sukiasyan,Sean M Kim,Cristina Godio,Julia M Bittencourt,Michael Cameron,Andrea Galmozzi,Stefano Forli,Dennis W Wolan,Benjamin F Cravatt,Dale L Boger,Enrique Saez

    Activity-based protein profiling (ABPP) has been used extensively to discover and optimize selective inhibitors of enzymes. Here, we show that ABPP can also be implemented to identify the converse—small-molecule enzyme activators. Using a kinetically controlled, fluorescence polarization-ABPP assay, we identify compounds that stimulate the activity of LYPLAL1—a poorly characterized serine hydrolase

    更新日期:2020-06-08
  • Comparative tRNA sequencing and RNA mass spectrometry for surveying tRNA modifications.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-08
    Satoshi Kimura,Peter C Dedon,Matthew K Waldor

    Chemical modifications of the nucleosides that comprise transfer RNAs are diverse. However, the structure, location and extent of modifications have been systematically charted in very few organisms. Here, we describe an approach in which rapid prediction of modified sites through reverse transcription-derived signatures in high-throughput transfer RNA-sequencing (tRNA-seq) data is coupled with identification

    更新日期:2020-06-08
  • Publisher Correction: Complete reconstitution of the diverse pathways of gentamicin B biosynthesis.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-02
    Yeon Hee Ban,Myoung Chong Song,Jae-Yeon Hwang,Hea-Lyung Shin,Hak Joong Kim,Seung Kon Hong,Na Joon Lee,Je Won Park,Sun-Shin Cha,Hung-Wen Liu,Yeo Joon Yoon

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

    更新日期:2020-06-02
  • Rolf Huisgen (1920-2020).
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-02
    Dirk Trauner

    Rolf Huisgen left us on 26 March 2020, just three months shy of his 100th birthday. His work has had an enormous influence on chemical biology, ranging from new methods for the synthesis of chemical probes to “click chemistry” and its application to in vivo bioconjugation.

    更新日期:2020-06-02
  • An allosteric modulator binds to a conformational hub in the β2 adrenergic receptor.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-01
    Xiangyu Liu,Jonas Kaindl,Magdalena Korczynska,Anne Stößel,Daniela Dengler,Markus Stanek,Harald Hübner,Mary J Clark,Jake Mahoney,Rachel Ann Matt,Xinyu Xu,Kunio Hirata,Brian K Shoichet,Roger K Sunahara,Brian K Kobilka,Peter Gmeiner

    Most drugs acting on G-protein-coupled receptors target the orthosteric binding pocket where the native hormone or neurotransmitter binds. There is much interest in finding allosteric ligands for these targets because they modulate physiologic signaling and promise to be more selective than orthosteric ligands. Here we describe a newly developed allosteric modulator of the β2-adrenergic receptor (β2AR)

    更新日期:2020-06-01
  • Site-specific ubiquitination affects protein energetics and proteasomal degradation.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-01
    Emma C Carroll,Eric R Greene,Andreas Martin,Susan Marqusee

    Changes in the cellular environment modulate protein energy landscapes to drive important biology, with consequences for signaling, allostery and other vital processes. The effects of ubiquitination are particularly important because of their potential influence on degradation by the 26S proteasome. Moreover, proteasomal engagement requires unstructured initiation regions that many known proteasome

    更新日期:2020-06-01
  • Selective N-glycan editing on living cell surfaces to probe glycoconjugate function.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-01
    Feng Tang,Mang Zhou,Ken Qin,Wei Shi,Ansor Yashinov,Yang Yang,Liyun Yang,Dongliang Guan,Lei Zhao,Yubo Tang,Yujie Chang,Lifen Zhao,Huaiyu Yang,Hu Zhou,Ruimin Huang,Wei Huang

    Cell surfaces are glycosylated in various ways with high heterogeneity, which usually leads to ambiguous conclusions about glycan-involved biological functions. Here, we describe a two-step chemoenzymatic approach for N-glycan-subtype-selective editing on the surface of living cells that consists of a first ‘delete’ step to remove heterogeneous N-glycoforms of a certain subclass and a second ‘insert’

    更新日期:2020-06-01
  • Pyridoxal-5'-phosphate-dependent alkyl transfer in nucleoside antibiotic biosynthesis.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-01
    Zheng Cui,Jonathan Overbay,Xiachang Wang,Xiaodong Liu,Yinan Zhang,Minakshi Bhardwaj,Anke Lemke,Daniel Wiegmann,Giuliana Niro,Jon S Thorson,Christian Ducho,Steven G Van Lanen

    Several nucleoside antibiotics are structurally characterized by a 5″-amino-5″-deoxyribose (ADR) appended via a glycosidic bond to a high-carbon sugar nucleoside (5′S,6′S)-5′-C-glycyluridine (GlyU). GlyU is further modified with an N-alkylamine linker, the biosynthetic origin of which has yet to be established. By using a combination of feeding experiments with isotopically labeled precursors and characterization

    更新日期:2020-06-01
  • Identification of a potent and selective covalent Pin1 inhibitor.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-06-01
    Benika J Pinch,Zainab M Doctor,Behnam Nabet,Christopher M Browne,Hyuk-Soo Seo,Mikaela L Mohardt,Shingo Kozono,Xiaolan Lian,Theresa D Manz,Yujin Chun,Shin Kibe,Daniel Zaidman,Dina Daitchman,Zoe C Yeoh,Nicholas E Vangos,Ezekiel A Geffken,Li Tan,Scott B Ficarro,Nir London,Jarrod A Marto,Stephen Buratowski,Sirano Dhe-Paganon,Xiao Zhen Zhou,Kun Ping Lu,Nathanael S Gray

    Peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1) is commonly overexpressed in human cancers, including pancreatic ductal adenocarcinoma (PDAC). While Pin1 is dispensable for viability in mice, it is required for activated Ras to induce tumorigenesis, suggesting a role for Pin1 inhibitors in Ras-driven tumors, such as PDAC. We report the development of rationally designed peptide inhibitors

    更新日期:2020-06-01
  • PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-05-25
    Sreekanth Rajan,Yongwoo Jang,Chun-Hyung Kim,Woori Kim,Hui Ting Toh,Jeha Jeon,Bin Song,Aida Serra,Julien Lescar,Jun Yeob Yoo,Serap Beldar,Hong Ye,Congbao Kang,Xue-Wei Liu,Melissa Feitosa,Yeahan Kim,Dabin Hwang,Geraldine Goh,Kah-Leong Lim,Hye Min Park,Choong Hwan Lee,Sungwhan F Oh,Gregory A Petsko,Ho Sup Yoon,Kwang-Soo Kim

    The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å

    更新日期:2020-05-25
  • m6A-binding YTHDF proteins promote stress granule formation.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-05-25
    Ye Fu,Xiaowei Zhuang

    Diverse RNAs and RNA-binding proteins form phase-separated, membraneless granules in cells under stress conditions. However, the role of the prevalent mRNA methylation, m6A, and its binding proteins in stress granule (SG) assembly remain unclear. Here, we show that m6A-modified mRNAs are enriched in SGs, and that m6A-binding YTHDF proteins are critical for SG formation. Depletion of YTHDF1/3 inhibits

    更新日期:2020-05-25
  • Structural insights into β-1,3-glucan cleavage by a glycoside hydrolase family.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-05-25
    Camila R Santos,Pedro A C R Costa,Plínio S Vieira,Sinkler E T Gonzalez,Thamy L R Correa,Evandro A Lima,Fernanda Mandelli,Renan A S Pirolla,Mariane N Domingues,Lucelia Cabral,Marcele P Martins,Rosa L Cordeiro,Atílio T Junior,Beatriz P Souza,Érica T Prates,Fabio C Gozzo,Gabriela F Persinoti,Munir S Skaf,Mario T Murakami

    The fundamental and assorted roles of β-1,3-glucans in nature are underpinned on diverse chemistry and molecular structures, demanding sophisticated and intricate enzymatic systems for their processing. In this work, the selectivity and modes of action of a glycoside hydrolase family active on β-1,3-glucans were systematically investigated combining sequence similarity network, phylogeny, X-ray crystallography

    更新日期:2020-05-25
  • Voices of chemical biology.
    Nat. Chem. Biol. (IF 12.587) Pub Date : 2020-05-22

    We asked a collection of chemical biologists, “What was the most exciting research achievement or technology innovation in chemical biology in the last five years?” and reveal some of the perspectives we received.

    更新日期:2020-05-22
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