The activity of the serotonin type 3 (5-HT3) receptor is associated with neurodegenerative, inflammatory and metabolic diseases, neuropsychiatric disorders, and cancer. Structural analysis of modulators of this receptor is likely to aid in future medicinal chemistry studies aimed at developing lead molecules targeting this receptor. Here we report the structure of a cone snail venom peptide that was

Paraquat is a fast-acting non-selective herbicide widely used globally to eradicate weeds. The emergence of weed resistance has fueled the drive to understand molecular mechanistic aspects and develop crops resistant to the herbicide. The transport of paraquat is mediated by members of the L-amino acid transporter family and are prime targets for the development of resistance. However, these transporters

Single alpha-helices (SAHs) are protein regions with unique mechanical properties, forming long stable monomeric helical structures in solution. To date, only a few naturally occurring SAH regions have been extensively characterized, primarily from myosins, leaving the structural and dynamic variability of SAH regions largely unexplored. Drebrin (developmentally regulated brain protein) contains a

The oncoprotein c-Myc is overexpressed or mutated in a large fraction of human cancers. The stability of c-Myc is controlled by phosphorylation of T58 and S62 within a conserved degron motif in the N-terminal transactivation domain, which triggers recruitment of the SCF ubiquitin ligase. The kinase Aurora A (AurA) has been shown to bind to both c-Myc and its paralog N-Myc and to promote their stability

The adaptor protein, Speckle-type BTB/POZ protein (SPOP), recruits substrates to the cullin-3-subclass of E3 ligase for selective protein ubiquitylation. The Myddosome protein, Myeloid differentiation primary response 88 (MyD88), is ubiquitylated by the SPOP-based E3 ligase to negatively regulate immune signaling, however, the sequence rules for SPOP-mediated substrate engagement and degradation are

Histones play a fundamental role in eukaryotic organisms not only as scaffolding proteins in DNA packaging but also in regulating gene expression. They constitute the protein reel around which DNA wraps forming nucleosomes. This initial packing gives rise to the chromatin fiber which is next folded into three-dimensional arrangements. Additionally, histones have expanded their functions through the

Quinone reductase 2 (NQO2) is a FAD-linked enzyme that cannot use the common reducing cofactors, NADH and NADPH, for efficient catalysis. This is unusual for an oxidoreductase, particularly since it is a member of a large family of enzymes that all use NAD(P)H efficiently to catalyse the two-electron reduction in quinones and other electrophiles. The inability of NQO2 to use NAD(P)H efficiently raises

There is an increasing interest in the role of fructose as a major driver of non-alcoholic fatty liver disease (NAFLD), and it is linked closely with the intake of sugar. However, there has also been the recognition that fructose can be produced directly from intracellular glucose via the evolutionarily conserved polyol pathway whose access is governed by aldose reductase (AR). The purpose of this

The concept of higher-order assembly signalling or signalling by co-operative assembly formation (SCAF) was proposed based on the structures of signalling assemblies formed by proteins featuring domains from the death-fold family and the Toll/interleukin-1 receptor domain family. Because these domains form filamentous assemblies upon stimulation and activate downstream pathways through induced proximity

Three-prime repair exonuclease 1 (TREX1) is a 3'-5' exonuclease that plays an important role in clearing cytoplasmic DNA. Additionally, TREX1 is translocated to the nucleus after DNA damage and assists in DNA repair. In this work, we evaluated the activity of TREX1 in the context of the removal of methyl DNA adducts. We observed that TREX1 was less efficient at degrading methyl methanesulfonate (MMS)-treated

Both mouse double-minute 2 (MDM2), an E3 ubiquitin ligase, and its closely related paralog, MDM4, which lacks E3 activity, play central roles in cellular homeostasis. MDM-linked dysfunction is associated with an increased risk of oncogenesis, primarily through targeting the tumor suppressor protein p53 for ubiquitination and degradation. Recent studies have revealed multifaceted roles of MDM proteins

Telomeres, essential for maintaining genomic stability, are typically preserved through the action of telomerase, a ribonucleoprotein complex that synthesizes telomeric DNA. One of its two core components, telomerase RNA (TR), serves as the template for this synthesis, and its evolution across different species is both complex and diverse. This review discusses recent advancements in understanding

The N6-methyladenine (6mA) modification is an essential epigenetic marker and plays a crucial role in processes, such as DNA repair, replication, and gene expression regulation. YerA from Bacillus subtilis is considered a novel class of enzymes that are capable of catalyzing the deamination of 6mA to produce hypoxanthine. Despite the significance of this type of enzymes in bacterial self-defense system

Family 1 Coenzyme A transferases (CtfAB) from the extremely thermophilic bacterium, Thermosipho melanesiensis, has been used for in vivo acetone production up to 70°C. This enzyme has tentatively been identified as the rate-limiting step, due to its relatively low-binding affinity for acetate. However, existing kinetic and mechanistic studies on this enzyme are insufficient to evaluate this hypothesis

The sulfosugar sulfoquinovose (SQ) is catabolized through the sulfoglycolytic Entner-Doudoroff pathway, beginning with the oxidation of SQ to sulfogluconolactone by SQ dehydrogenase. We present a comprehensive structural and kinetic characterization of Pseudomonas putida SQ dehydrogenase (PpSQDH). PpSQDH is a tetrameric enzyme belonging to the short-chain dehydrogenase/reductase (SDR) superfamily with

DNA-joining by ligase and polymerase enzymes has provided the foundational tools for generating recombinant DNA and enabled the assembly of gene and genome-sized synthetic products. Xenobiotic nucleic acid (XNA) analogues of DNA and RNA with alternatives to the canonical bases, so-called 'unnatural' nucleobase pairs (UBP-XNAs), represent the next frontier of nucleic acid technologies, with applications

Thiamin, an essential micronutrient, is a cofactor for enzymes involved in the central carbon metabolism and amino acid pathways. Despite efforts to enhance thiamin content in rice by incorporating thiamin biosynthetic genes, increasing thiamin content in the endosperm remains challenging, possibly due to a lack of thiamin stability and/or a local sink. The introduction of storage proteins has been

The Stenotrophomonas maltophilia L2 cephalosporinase is one of two beta-lactamases that afford S. maltophilia beta-lactam resistance. With the overuse of beta-lactams, selective pressures have contributed to the evolution of these proteins, generating proteins with an extended spectrum of activity. Variant L2 cephalosporinases have been detected, as has their distribution into two main clades (clades

The sodium phosphate cotransporter-2A (NPT2A) mediates basal and parathyroid hormone (PTH)- and fibroblast growth factor-23 (FGF23)-regulated phosphate transport in proximal tubule cells of the kidney. Both basal and hormone-sensitive transport require sodium hydrogen exchanger regulatory factor-1 (NHERF1), a scaffold protein with tandem PDZ domains, PDZ1 and PDZ2. NPT2A binds to PDZ1. RGS14 persistently

Type VI secretion systems (T6SSs) are widespread bacterial protein secretion machines that inject toxic effector proteins into nearby cells, thus facilitating both bacterial competition and virulence. Pseudomonas aeruginosa encodes three evolutionarily distinct T6SSs that each export a unique repertoire of effectors. Owing to its genetic tractability, P. aeruginosa has served as a model organism for

In mammals, molecular mechanisms of circadian rhythms involve a time-delayed negative feedback loop generating autonomous oscillations of ∼24 h. Most cell types in mammals possess circadian rhythms regulating temporal organization of cellular and physiological processes. Intriguingly, pluripotent stem cells do not possess circadian rhythms and oscillations arise after a defined period of differentiation

Ischemia-reperfusion injury (IRI) occurs when the blood supply to an organ is temporarily reduced and then restored. Kidney IRI is a form of acute kidney injury (AKI), which often progresses to kidney fibrosis. Necroptosis is a regulated necrosis pathway that has been implicated in kidney IRI. Necroptotic cell death involves the recruitment of the RIPK1 and RIPK3 kinases and the activation of the terminal

Advances in solid-state nuclear magnetic resonance (ssNMR) spectroscopy and cryogenic electron microscopy (cryoEM) have revealed the polymorphic nature of the amyloid state of proteins. Given the association of amyloid with protein misfolding disorders, it is important to understand the principles underlying this polymorphism. To address this problem, we combined computational tools to predict the

Regulation of protein longevity via the ubiquitin (Ub) - proteasome pathway is fundamental to eukaryotic biology. Ubiquitin E3 ligases (E3s) interact with substrate proteins and provide specificity to the pathway. A small subset of E3s bind to specific exposed N-termini (N-degrons) and promote the ubiquitination of the bound protein. Collectively these E3s, and other N-degron binding proteins, are

The phosphatases of regenerating liver (PRLs) are members of the protein tyrosine phosphatase (PTP) superfamily that play pro-oncogenic roles in cell proliferation, migration, and survival. We previously demonstrated that PRLs can post-translationally down-regulate PTEN, a tumor suppressor frequently inactivated in human cancers, by dephosphorylating PTEN at Tyr336, which promotes the NEDD4-mediated

A dense glycocalyx, composed of the megaDalton-sized membrane mucin MUC17, coats the microvilli in the apical brush border of transporting intestinal epithelial cells, called enterocytes. The formation of the MUC17-based glycocalyx in the mouse small intestine occurs at the critical suckling-weaning transition. The glycocalyx extends 1 µm into the intestinal lumen and prevents the gut bacteria from

Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria, allowing for adjustments in cellular energy metabolism to maintain metabolic homeostasis. Small molecule uncouplers have been extensively studied for their potential to increase metabolic rate, and recent research has focused on developing safe and effective mitochondrial uncoupling agents for the treatment of

Geobacter's unique ability to perform extracellular electron transfer (EET) to electrodes in microbial fuel cells (MFCs) has sparked the implementation of sustainable production of electrical energy. However, the electrochemical performance of Geobacter's biofilms in MFCs remains challenging to implement industrially. Multiple approaches are being investigated to enhance MFC technologies. Protein engineering

Myofibroblast differentiation, characterized by accumulation of cytoskeletal and extracellular matrix proteins by fibroblasts, is a key process in wound healing and pathogenesis of tissue fibrosis. Transforming growth factor-β (TGF-β) is the most powerful known driver of myofibroblast differentiation. TGF-β signals through transmembrane receptor serine/threonine kinases that phosphorylate Smad transcription

Conditions of endoplasmic reticulum (ER) stress reduce protein synthesis by provoking translation regulation, governed by the eIF2α kinase PERK. When PERK is inhibited during ER stress, retention of a selective subset of glycoproteins occurs, a phenomenon we termed selective ER retention (sERr). sERr clients are enriched with tyrosine kinase receptors (RTKs), which form large molecular weight disulfide

Per- and polyfluorinated chemicals (PFAS) are of rising concern due to environmental persistence and emerging evidence of health risks to humans. Environmental persistence is largely attributed to a failure of microbes to degrade PFAS. PFAS recalcitrance has been proposed to result from chemistry, specifically C-F bond strength, or biology, largely negative selection from fluoride toxicity. Given natural

Peroxiredoxin 6 (PRDX6) is a multifunctional enzyme involved in phospholipid peroxide repair and metabolism. In this study we investigated the global lipid composition of a human hepatocarcinoma cell line SNU475 lacking PRDX6 and lipid related cellular processes. There was a general decrease in multiple lipids species upon loss of PRDX6, in particular sphingomyelins and acylcarnitines, consistent with

Despite extensive research, strategies to effectively combat breast cancer stemness and achieve a definitive cure remains elusive. CD44, a well-defined cancer stem cell (CSC) marker is reported to promote breast cancer tumorigenesis, metastasis, and chemoresistance. However, mechanisms leading to its enhanced expression and function is poorly understood. Here, we demonstrate that USP10 positively regulates

Bacteria evolve mechanisms to compete for limited resources and survive in new niches. Here we study the mechanism of isethionate import from the sulfate-reducing bacterium Oleidesulfovibrio alaskensis. The catabolism of isethionate by Desulfovibrio species has been implicated in human disease, due to hydrogen sulfide production, and has potential for industrial applications. O. alaskensis employs

The active site Cys residue in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is sensitive to oxidation by hydrogen peroxide (H2O2), with this resulting in enzyme inactivation. This re-routes the carbon flux from glycolysis to the pentose phosphate pathway favoring the formation of NADPH and synthetic intermediates required for antioxidant defense and repair systems. Consequently, GAPDH inactivation

Protein kinase A (PKA) is a basophilic kinase implicated in the modulation of many cell-signaling and physiological processes. PKA also contributes to cancer-relevant events such as growth factor action, cell cycle control, cell migration and tumor metabolism. Germline and somatic mutations in PKA, gene amplifications, and chromosome rearrangements that encode kinase fusions, are linked to a growing

Erythrokeratodermia variabilis et progressiva (EKVP) is a rare hereditary skin disorder characterized by hyperkeratotic plaques and erythematous patches that progressively worsen with age. This disorder has been associated with variants in three connexin encoding genes (GJA1, GJB3, GJB4) and four unrelated genes (KRT83, KDSR, TRPM4, PERP). Most cases of connexin-linked EKVP exhibit an autosomal dominant

Glycation-induced stress (G-iS) is a physiological phenomenon that leads to the formation of advanced glycation end-products, triggering detrimental effects such as oxidative stress, inflammation, and damage to intracellular structures, tissues, and organs. This process is particularly relevant because it has been associated with various human pathologies, including cancer, neurodegenerative diseases

G protein-coupled receptors (GPCRs) serve as critical communication hubs, translating a wide range of extracellular signals into intracellular responses that govern numerous physiological processes. In class-A GPCRs, conserved motifs mediate conformational changes of the active states of the receptor, and signal transduction is achieved by selectively binding to Gα proteins and/or adapter protein,

Protein arginine methyltransferase 3 (PRMT3), a type I arginine methyltransferase is localized predominantly in the cytoplasm and regulates different cellular functions. Nevertheless, PRMT3 also exhibits regulatory functions in the nucleus by interacting with the liver X receptor alpha (LXRα) and catalyzes asymmetric dimethylation modifications at arginine 3 of histone 4 (H4R3me2a). However, very little

Lamins form a proteinaceous meshwork as a major structural component of the nucleus. Lamins, along with their interactors, act as determinants for chromatin organization throughout the nucleus. The major dominant missense mutations responsible for autosomal dominant forms of muscular dystrophies reside in the Ig fold domain of lamin A. However, how lamin A contributes to the distribution of heterochromatin

Sequence variation among homologous proteins can shed light on their function and ancestry. In this study, we analyze variation at catalytic residues among MCR (mobile colistin resistance) proteins, which confer resistance to the last resort antibiotic, colistin, in gram-negative bacteria. We show that not all naturally occurring variants at a lipid A-binding residue, Ser284, are tolerated in MCR-1

Gasdermin D (GSDMD) is the chief executioner of inflammatory cell death or pyroptosis. During pyroptosis, proteolytic processing of GSDMD releases its N-terminal domain (NTD), which then forms large oligomeric pores in the plasma membranes. Membrane pore-formation by NTD allows the release of inflammatory cytokines and causes membrane damage to induce cell death. Structural mechanisms of GSDMD-mediated

PI3Kα, consisting of the p110α isoform of the catalytic subunit of PI 3-kinase (encoded by PIK3CA) and the p85α regulatory subunit (encoded by PI3KR1) is activated by growth factor receptors. The identification of common oncogenic mutations in PIK3CA has driven the development of many inhibitors that bind to the ATP-binding site in the p110α subunit. Upon activation, PI3Kα undergoes conformational

Existing literature suggests that infection-specific mechanisms may play a significant role in the onset and progression of dementia, as opposed to the broader phenomenon of systemic inflammation. In addition, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors have been proposed as a potential therapeutic approach for sepsis, given their anti-inflammatory and antioxidant properties

The nitrogen-fixing rhizobia-legume symbiosis relies on a complex interchange of molecular signals between the two partners during the whole interaction. On the bacterial side, different surface polysaccharides, such as lipopolysaccharide (LPS) and exopolysaccharide (EPS), might play important roles for the success of the interaction. In a previous work we studied two Sinorhizobium fredii HH103 mutants

Myc proteins are transcription factors crucial for cell proliferation. They have a C-terminal domain that mediates Max and DNA binding, and an N-terminal disordered region culminating in the transactivation domain (TAD). The TAD participates in many protein-protein interactions, notably with kinases that promote stability (Aurora-A) or degradation (ERK1, GSK3) via the ubiquitin-proteasome system. We

In recent years, significant strides in both conceptual understanding and technological capabilities have bolstered our comprehension of the factors underpinning cancer initiation and progression. While substantial insights have unraveled the molecular mechanisms driving carcinogenesis, there has been an overshadowing of the critical contribution made by epigenetic pathways, which works in concert

Establishing, maintaining, and removing histone post-translational modifications associated with heterochromatin is critical for shaping genomic structure and function as a cell navigates different stages of development, activity, and disease. Dynamic regulation of the repressive chromatin landscape has been documented in several key cell states - germline cells, activated immune cells, actively replicating

Therapeutically, targeting the pro- and anti-apoptotic proteins has been one of the major approaches behind devising strategies to combat associated diseases. Human high-temperature requirement serine protease A2 (hHtrA2), which induces apoptosis through both caspase-dependent and independent pathways is implicated in several diseases including cancer, ischemic heart diseases, and neurodegeneration

The cytosolic glutathione-degrading enzyme, ChaC1, is highly up-regulated in several cancers, with the up-regulation correlating to poor prognosis. The ability to inhibit ChaC1 is therefore important in different pathophysiological situations, but is challenging owing to the high substrate Km of the enzyme. As no inhibitors of ChaC1 are known, in this study we have focussed on this goal. We have initially

Adaptor proteins play central roles in the assembly of molecular complexes and co-ordinated activation of specific pathways. Through their modular domain structure, the NCK family of adaptor proteins (NCK1 and NCK2) link protein targets via their single SRC Homology (SH) 2 and three SH3 domains. Classically, their SH2 domain binds to phosphotyrosine motif-containing receptors (e.g. receptor tyrosine

Histone deacetylase 7 (HDAC7) is a member of the class IIa family of classical HDACs with important roles in cell development, differentiation, and activation, including in macrophages and other innate immune cells. HDAC7 and other class IIa HDACs act as transcriptional repressors in the nucleus but, in some cell types, they can also act in the cytoplasm to modify non-nuclear proteins and/or scaffold

The enzyme serine hydroxymethyltransferase (SHMT) plays a key role in folate metabolism and is conserved in all kingdoms of life. SHMT is a pyridoxal 5'-phosphate (PLP) - dependent enzyme that catalyzes the conversion of L-serine and (6S)-tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. Crystal structures of multiple members of the SHMT family have shown that the enzyme has a single

The pursuit of novel therapeutics is a complex and resource-intensive endeavor marked by significant challenges, including high costs and low success rates. In response, drug repositioning strategies leverage existing FDA-approved compounds to predict their efficacy across diverse diseases. Peptidyl arginine deiminase 4 (PAD4) plays a pivotal role in protein citrullination, a process implicated in