Proteins-Structure Function and Bioinformatics最新文献

{"title":"The Mycobacterium tuberculosis Rv0132c Gene Product Mtb-FGD2 Can Act as an F₄₂₀-Dependent Glucose Dehydrogenase.","authors":"Adewale V Aderemi, Matthew Snee, Richard B Tunnicliffe, Linus O Johanissen, Matthew J Cliff, Colin W Levy, Derren J Heyes, Marina Golovanova, Thomas A Jowitt, Sam Hay, Andrew W Munro, Jonathan P Waltho, David Leys","doi":"10.1002/prot.70139","DOIUrl":"https://doi.org/10.1002/prot.70139","url":null,"abstract":"<p><p>The role of the cell envelope-associated Rv0132c/FGD2 from Mycobacterium tuberculosis has long been a subject of debate. Importantly, FGD2 is found only in pathogenic mycobacteria, making it a potential drug target. While some suggest it functions as a glucose-6-phosphate dehydrogenase, others propose it acts instead as an F₄₂₀-dependent hydroxy-mycolic acid dehydrogenase-an activity linked to cell-wall remodeling and inhibition by the anti-tubercular drug pretomanid. Yet, direct evidence for either activity has been lacking. Here, we heterologously express and purify active Mtb-FGD2, and demonstrate that the enzyme binds the F₄₂₀ cofactor with nanomolar affinity. Crystal structures for both the apo-form and the F₄₂₀ complex reveal that the Mtb-FGD2 active site architecture is consistent with sugar substrates but notably lacks a phosphate-binding pocket. Biochemical assays confirm that Mtb-FGD2 functions efficiently as an F₄₂₀-dependent glucose dehydrogenase in vitro. Computational docking combined with molecular dynamics simulations further supports the formation of a catalytically plausible β-D-glucose:F₄₂₀ ternary complex. When coupled to other F₄₂₀-dependent enzymes, Mtb-FGD2 readily supports glucose-driven F₄₂₀.H₂-dependent oxidoreductase activity. Our data thus suggest that the Mtb-FGD2 provides reduced F₄₂₀.H₂ in a glucose-dependent manner to support mycobacterial F₄₂₀.H₂-dependent oxidoreductases in the cell envelope.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay of Ser273 Phosphorylation and K268 and K293 Acetylation in PPARγ: Implications for PPARγ Activation.","authors":"Caique Camargo Malospirito, Marieli Mariano Gonçalves Dias, Gabriel Ernesto Jara, Thayná Mendonça Avelino, Giovanna Blazutti Elias, Paulo Sergio Lopes de Oliveira, Ana Carolina Migliorini Figueira","doi":"10.1002/prot.70140","DOIUrl":"10.1002/prot.70140","url":null,"abstract":"<p><p>Post-translational modifications (PTMs) play a critical role in regulating the transcriptional activity of PPARγ, a nuclear receptor central to glucose and lipid homeostasis. Among these, lysine acetylation at K268 and K293 and phosphorylation at S273 are particularly relevant to insulin sensitivity. These residues form a regulatory binding interface for protein partners such as SIRT1 and CDK5, which exert opposing effects on PPARγ activity-SIRT1 promoting deacetylation and insulin sensitization, and CDK5 driving phosphorylation linked to insulin resistance. Here we show that modifications at this interface influence PPARγ's interaction with its regulators and its transcriptional activity. Acetyl-mimetic mutations at K268 and K293 reduce CDK5 binding and phosphorylation, while enhancing transcriptional activity. Phosphorylation at S273 weakens SIRT1 binding and limits its repressive function, even under overexpression. These effects likely reflect both direct interference with protein docking and changes in the global acetylation or phosphorylation landscape. Our findings reveal that this PTM-rich interface functions as a regulatory hub, integrating signals from multiple protein partners to fine-tune PPARγ activity. Unlike full receptor activation by agonists, which often triggers adverse effects, modulating this interface represents a refined therapeutic avenue for enhancing insulin sensitivity in metabolic diseases like obesity and type 2 diabetes, with improved specificity and reduced side effects.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147679175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved Method for Predicting GPCR-GPCR Interaction Pairs.","authors":"Aoi Fukushima, Arina Ouma, Hiroki Teruse, Hiroyuki Toh, Wataru Nemoto","doi":"10.1002/prot.70138","DOIUrl":"https://doi.org/10.1002/prot.70138","url":null,"abstract":"<p><p>G protein-coupled receptors (GPCRs) can form oligomers, which activate distinct signaling pathways compared to monomeric GPCRs. Oligomerization influences GPCR trafficking, ligand affinity, and signal transduction, and has been implicated in diseases such as schizophrenia and hypertension. Understanding GPCR oligomerization is essential for uncovering disease mechanisms and developing new therapeutic strategies. Previously, we developed a GPCR-GPCR interaction pair predictor (GGIP) utilizing an SVM algorithm. Features for the predictor were generated by quantifying amino acid properties, assigning scores, and averaging these values across the target sequences. In this study, we aimed to enhance the predictive accuracy of GGIP. We evaluated four methods by combining two feature generation techniques with two prediction algorithms. We tested the sequence segmentation-based method from our previous work and automatic feature generation using amino acid sequences with an autoencoder while evaluating both the SVM and gradient-boosting decision tree (GBDT) as prediction algorithms. Combining segmentation-based feature generation with GBDT yielded the highest performance, achieving an AUROC of over 0.98. Some features could be identified as a basis for predicting that a pair of GPCRs would interact, based on amino acid properties and their arrangement in the three-dimensional structure. Integrating our improved method with disease-related gene expression variation data revealed a significant association between GPCR interaction pairs and the presence of disease-related differentially expressed genes (DEGs). Specifically, around 90% of experimentally determined interaction pairs contained at least one protomer gene classified as a disease-related DEG, suggesting that GPCRs forming interaction pairs are more likely to be associated with disease-related gene expression changes. Among these pairs, we identified the interaction between mGluR2 and 5-HT2AR, which has been postulated to be linked to schizophrenia. Although this association was not registered in the database, we were able to confirm it through published literature. Given the significant association with disease-related DEGs, this approach is critical for identifying disease-associated GPCR interaction pairs and guiding future therapeutic developments.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147647532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic, Proteomic, and Structural Insights Into the Transition of FtsZ From Thermophiles to Mesophiles Across the Prokaryotic Kingdom.","authors":"Dipanjan Ghosh, Prithvi Basak, Sukhendu Mandal, Gopal Chakrabarti","doi":"10.1002/prot.70136","DOIUrl":"https://doi.org/10.1002/prot.70136","url":null,"abstract":"<p><p>Understanding how cellular macromolecules adapt in thermophilic and mesophilic organisms across different thermal environments provides important insights into evolutionary mechanisms. These mechanisms enable early life forms to maintain essential biological processes in diverse ecological niches. FtsZ, an important protein for bacterial and archaeal cell division, has evolved to function across different thermal environments. The present study investigates the genomic, proteomic, and structural adaptations of the pivotal bacterial cell division protein FtsZ during the transition from thermophilic to mesophilic bacteria across the prokaryotic kingdom. Through comprehensive analyses, we reveal intricate evolutionary dynamics, shedding light on the molecular strategies that underlie bacterial adaptation to diverse thermal environments. Our genomic exploration unveils key genetic variations correlating with temperature preferences, while proteomic investigations elucidate distinct expression patterns of FtsZ in response to thermal shifts. Structural insights show temperature-dependent alterations in the conformation of these proteins, providing a nuanced understanding of their functional adaptations. These findings collectively contribute to our comprehension of the molecular mechanisms governing bacterial evolution and highlight the importance of FtsZ in temperature-driven adaptations across prokaryotes. We found that three amino acids, namely lysine (K), leucine (L), and isoleucine (I), are particularly enriched in thermophilic FtsZ protein sequences compared with those of mesophiles. In addition, the mutational changes occurred in the thermophilic FtsZ protein structure to understand the thermal stability of the protein. Simultaneously, the B-factor and T_m value, these two essential parameters, established that the mutant FtsZ structures were thermodynamically unstable for losing those distinct amino acids.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147629227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In Silico Structure-Guided Design of Peptide Candidates Targeting γ-Secretase Subunit Assembly.","authors":"Selcen Arı Yuka, Kübra Telli, Alper Yılmaz","doi":"10.1002/prot.70137","DOIUrl":"https://doi.org/10.1002/prot.70137","url":null,"abstract":"<p><p>The γ-secretase complex is a membrane-embedded protease essential for intramembrane cleavage of substrates such as Notch receptors and the amyloid precursor protein (APP), processes central to cancer progression and Alzheimer's disease (AD) pathology. However, catalytic inhibition of γ-secretase disrupts multiple signaling pathways, resulting in dose-limiting toxicities. In this study, we report a structure-guided approach to generate peptides with binding and stability profiles that disrupt the assembly of γ-secretase by targeting the interactions of Presenilin-1 and Nicastrin with APH1. First, molecular docking was performed for 36 248 peptides of varying lengths to assess their affinity scores to the PS1 and NCT interaction regions of APH1. Peptides filtered based on their affinity scores and physicochemical properties were then subjected to global molecular docking. 50-nanosecond molecular dynamics simulations and MM/PBSA analyses were performed on the top 10 potential candidates, identifying those with high dynamic interaction potential. Thus, seven γ-secretase inhibitor candidates with favorable affinity scores capable of providing stable interactions and thereby having the potential to disrupt the APH1:PS1 assembly were identified. This approach, which overcomes the challenges of targeting the transmembrane catalytic domain, is based on the inhibition of subunit assembly and presents promising candidates for future experimental studies.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":2.8,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Large Extent of Convergent Evolution Towards the Double Histone Fold Revealed by Targeted Sequence and Structure Search Approach.","authors":"Toshiko Miyake, Anna Ranaudo, Elena Sacco, Claudio Greco","doi":"10.1002/prot.70081","DOIUrl":"10.1002/prot.70081","url":null,"abstract":"<p><p>Histone proteins are key players in chromatin packaging. In eukaryotes, nucleosomal cores-the DNA packaging fundamental units-are formed by composition of histone dimers. The double histone fold is a protein structure where two consecutive regions, each featuring histone fold, come together to create a histone pseudodimer. Although regarded as an uncommon fold to date, in this study we show-by protein structure and sequence analyses-that the double histone fold is widespread in eukaryotes. Perspectives of such outcome are discussed in terms of novel directions that our results may open in diverse areas, from epigenetics to the design of DNA-binding proteins.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"875-882"},"PeriodicalIF":2.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145460724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biochemical, Biophysical, and Mechanistic Insights on a Putative Oxidoreductase From Mycobacterium tuberculosis That Shares Structural Homology With Tetracycline Destructase.","authors":"Mohd Shiraz, Dipanwita Biswas, G Priyanka, N Prakash Prabhu, Mohd Akif","doi":"10.1002/prot.70095","DOIUrl":"10.1002/prot.70095","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. The emergence of Mtb's multidrug-resistant and extremely drug-resistant strains has imposed a great challenge for TB treatment. Hence, there is always a demand to explore new targets that may be crucial for the survival and pathogenicity of the bacilli. Oxidoreductases are a class of enzymes that transfer electrons in various biological pathways and reactions, at the expense of cellular NADPH/NADH. Here, we analyzed oxidoreductases from the H37Rv proteome and identified two uncharacterized putative oxidoreductases, Rv1260 and Rv1714. These putative oxidoreductases showed conservation among pathogenic and opportunistic mycobacterial species and were predicted to be virulence factors essential for the pathogen's survival. The 3D structural model and amino acid sequence of one of the oxidoreductases, Rv1260, showed similarities with tetracycline destructase, a flavin-dependent monooxygenase. Thin-layer chromatography and UV-visible spectroscopic experiments confirmed the presence of the FAD molecule in a bound form with the recombinant protein. Fluorescence quenching studies demonstrated a comparatively better affinity of NADPH than NADH with the protein. The protein also displayed efficient binding with chlortetracycline. Molecular dynamics simulations were employed to gain insights into the substrate binding and conformational changes in the protein. Moreover, the importance of the substrate binding region, the C-terminal helix, and the FAD binding cavity, located near the isoalloxazine ring, was highlighted. Overall, the study provides biochemical, biophysical, and mechanistic insights into one of the putative Mtb oxidoreductases. Based on our data, we propose that this protein may perform monooxygenation functions under specific redox conditions and contribute to the redox processes in Mtb.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"999-1016"},"PeriodicalIF":2.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145688699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural Modeling and Dynamics of the Full-Length Homer1 Multimer.","authors":"Zsófia E Kálmán, András Czajlik, Brigitta Maruzs, Fanni Farkas, István Pap, Csilla Homonnay, Tomas Klumpler, Gyula Batta, Zoltán Gáspári, Bálint Péterfia","doi":"10.1002/prot.70091","DOIUrl":"10.1002/prot.70091","url":null,"abstract":"<p><p>Homer proteins are modular scaffold molecules that constitute an integral part of the protein network within the postsynaptic density. Full-length Homer1 forms a large homotetramer via a long coiled coil region, and can interact with proline-rich target sequences with its globular EVH1 domain. Here we report an atomistic model of the Homer1 coiled coil region along with the NMR solution structure and backbone dynamics of its EVH1 domain, with implications for the organization of the full-length tetramer. Compared to the already available EVH1 structures, our NMR ensemble exhibits subtle differences, mostly in and around its partner binding region, suggesting the presence of ligand-induced conformational transitions. Molecular dynamics simulations of the long coiled coil reveal distinct regions with different stability and flexibility, with the N-terminal part of the coiled coil exhibiting the largest motions. Interestingly, this segment is highly conserved, pointing to the functional relevance of the observed dynamical features. Our results indicate previously unexplored aspects of the flexibility of the full-length Homer1 tetramer that might contribute to the dynamic rearrangements of the postsynaptic protein network linked to its functional transitions.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"947-960"},"PeriodicalIF":2.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145566396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Protein Involved in Initiation 1 Interaction With Starch Synthase 4 From Arabidopsis thaliana Induces Inhibition of Elongating Activity.","authors":"Mélanie Bossu, Rayan Osman, Guillaume Brysbaert, Marc Ferdinand Lensink, David Dauvillée, Coralie Bompard","doi":"10.1002/prot.70089","DOIUrl":"10.1002/prot.70089","url":null,"abstract":"<p><p>Starch is the major energy storage compound in plants. It accumulates in the form of insoluble, partly crystalline granules whose number and shape are specific to each plant species. These characteristics are defined very early in starch biosynthesis, at the initiation stage. Starch biosynthesis initiation is a complex process that relies on the coordinated action of several proteins that interact together in the so-called complex of initiation. Starch Synthase 4 (SS4) is the only initiation protein with enzymatic activity. It catalyzes the formation of glucan primers, which serve as substrates for the enzymatic machinery that synthesizes starch granules. Previous studies have highlighted the importance of interactions between SS4 and regulatory proteins in this process. Among them, Protein Involved in Initiation 1 (PII1) interacts with SS4 but its function is not yet established. In this study, we explored the structural and functional implications of PII1 on SS4's enzymatic activity. Our findings reveal that PII1 contains a long coiled-coil domain that specifically interacts with SS4, leading to modification of SS4's glucan elongation activity. Importantly, this interaction is specific to SS4 and does not affect other known synthases, suggesting a targeted regulatory mechanism probably through a dimerization domain. This work describes the structural specificities of PII1 and SS4 and reveals a possible function for PII1 in the initiation complex.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"973-986"},"PeriodicalIF":2.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145589797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rieske Iron-Sulfur Cluster Proteins From an Anaerobic Ammonium Oxidizer Suggest Unusual Energetics in Their Parent Rieske/Cytochrome b Complexes.","authors":"David Hauser, Mandy Sode, Elena A Andreeva, Kristian Parey, Thomas R M Barends","doi":"10.1002/prot.70084","DOIUrl":"10.1002/prot.70084","url":null,"abstract":"<p><p>Anaerobic ammonium-oxidizing (anammox) bacteria employ a unique, hydrazine-based pathway to obtain energy from nitrite and ammonium. These organisms possess distinct Rieske/cytochrome b complexes whose precise role in anammox metabolism remains unclear, but which have been proposed to include the generation of NAD(P)H. This would require energetics and structural features unusual for such complexes. Here we present crystal structures and electrochemical investigations of the Rieske subunits of two of these complexes from the anammox organism Kuenenia stuttgartiensis, Kuste4569 and Kustd1480. Both proteins display high redox potentials (> + 300 mV), which can be in part explained by their crystal structures and which fit perfectly into the energetic scheme of the proposed NAD(P)H generation mechanism. Moreover, AlphaFold3 models of the parent complexes trace out a path for the electrons required for NAD(P)H production, which includes a proposed, novel b-type heme in the membrane-bound part of the complex.</p>","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"905-920"},"PeriodicalIF":2.8,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12954380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145497508","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}