Proteins-Structure Function and Bioinformatics最新文献_第10页

Unraveling the Structural Basis of Biased Agonism in the β₂-Adrenergic Receptor Through Molecular Dynamics Simulations. 通过分子动力学模拟揭示β2-肾上腺素能受体偏激激动的结构基础

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-03-01 Epub Date: 2024-11-16 DOI: 10.1002/prot.26766

Wojciech Plazinski, Aneta Archala, Krzysztof Jozwiak, Anita Plazinska

{"title":"Unraveling the Structural Basis of Biased Agonism in the β2-Adrenergic Receptor Through Molecular Dynamics Simulations.","authors":"Wojciech Plazinski, Aneta Archala, Krzysztof Jozwiak, Anita Plazinska","doi":"10.1002/prot.26766","DOIUrl":"10.1002/prot.26766","url":null,"abstract":"Biased agonism in G protein-coupled receptors is a phenomenon resulting in the selective activation of distinct intracellular signaling pathways by different agonists, which may exhibit bias toward either Gs, Gi, or arrestin-mediated pathways. This study investigates the structural basis of ligand-induced biased agonism within the context of the β2-adrenergic receptor (β2-AR). Atomistic molecular dynamics simulations were conducted for β2-AR complexes with two stereoisomers of methoxynaphtyl fenoterol (MNFen), that is, compounds eliciting qualitatively different cellular responses. The simulations reveal distinct interaction patterns within the binding cavity, dependent on the stereoisomer. These changes propagate to the intracellular parts of the receptor, triggering various structural responses: the dynamic structure of the intracellular regions of the (R,R)-MNFen complex more closely resembles the \"Gs-compatible\" and \"β-arrestin-compatible\" conformation of β2-AR, while both stereoisomers maintain structural responses equidistant from the inactive conformation. These findings are confirmed by independent coarse-grained simulations. In the context of deciphered molecular mechanisms, Trp313 plays a pivotal role, altering its orientation upon interactions with (R,R)-MNFen, along with the Lys305-Asp192 ionic bridge. This effect, accompanied by ligand interactions with residues on TM2, increases the strength of interactions within the extracellular region and the binding cavity, resulting in a slightly more open conformation and a minor (by ca. 0.2 nm) increase in the distance between the TM5-TM7, TM1-TM6, TM6-TM7, and TM1-TM5 pairs. On the other hand, an even slighter decrease in the distance between the TM1-TM4 and TM2-TM4 pairs is observed.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"728-744"},"PeriodicalIF":3.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142645237","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}

引用次数: 0

Insights Into the Molecular Interactions of MIC2 and M2AP: Role of TSR6 and Conservation Across Species. 洞察 MIC2 和 M2AP 的分子相互作用：TSR6 的作用和跨物种保护

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-03-01 Epub Date: 2024-10-22 DOI: 10.1002/prot.26758

Xu Xia, Chenqiang Du, Yang Wang, Gaojie Song

引用次数: 0

Unveiling the Complexity of cis-Regulation Mechanisms in Kinases: A Comprehensive Analysis. 揭示激酶顺式调节机制的复杂性：全面分析。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-03-01 Epub Date: 2024-10-04 DOI: 10.1002/prot.26751

Alvaro M Navarro, Macarena Alonso, Elizabeth Martínez-Pérez, Tamas Lazar, Toby J Gibson, Javier A Iserte, Peter Tompa, Cristina Marino-Buslje

{"title":"Unveiling the Complexity of cis-Regulation Mechanisms in Kinases: A Comprehensive Analysis.","authors":"Alvaro M Navarro, Macarena Alonso, Elizabeth Martínez-Pérez, Tamas Lazar, Toby J Gibson, Javier A Iserte, Peter Tompa, Cristina Marino-Buslje","doi":"10.1002/prot.26751","DOIUrl":"10.1002/prot.26751","url":null,"abstract":"Protein cis-regulatory elements (CREs) are regions that modulate the activity of a protein through intramolecular interactions. Kinases, pivotal enzymes in numerous biological processes, often undergo regulatory control via inhibitory interactions in cis. This study delves into the mechanisms of cis regulation in kinases mediated by CREs, employing a combined structural and sequence analysis. To accomplish this, we curated an extensive dataset of kinases featuring annotated CREs, organized into homolog families through multiple sequence alignments. Key molecular attributes, including disorder and secondary structure content, active and ATP-binding sites, post-translational modifications, and disease-associated mutations, were systematically mapped onto all sequences. Additionally, we explored the potential for conformational changes between active and inactive states. Finally, we explored the presence of these kinases within membraneless organelles and elucidated their functional roles therein. CREs display a continuum of structures, ranging from short disordered stretches to fully folded domains. The adaptability demonstrated by CREs in achieving the common goal of kinase inhibition spans from direct autoinhibitory interaction with the active site within the kinase domain, to CREs binding to an alternative site, inducing allosteric regulation revealing distinct types of inhibitory mechanisms, which we exemplify by archetypical representative systems. While this study provides a systematic approach to comprehend kinase CREs, further experimental investigations are imperative to unravel the complexity within distinct kinase families. The insights gleaned from this research lay the foundation for future studies aiming to decipher the molecular basis of kinase dysregulation, and explore potential therapeutic interventions.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"575-587"},"PeriodicalIF":3.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376308","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}

引用次数: 0

Based on Molecular Docking, Molecular Dynamics Simulation and MM/PB(GB)SA to Study Potential Inhibitors of PRRSV-Nsp4. 基于分子对接、分子动力学模拟和 MM/PB(GB)SA 研究 PRRSV-Nsp4 的潜在抑制剂

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-03-01 Epub Date: 2024-10-11 DOI: 10.1002/prot.26754

Tianyu Shi, Wenzhou Chang, Xinyu Wei, Yiling Kong, Ying Wei

引用次数: 0

Localized Amino Acid Enrichment Analysis as a Tool for Understanding Protein Extremophilicity. 局部氨基酸富集分析作为了解蛋白质极端亲水性的工具

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-03-01 Epub Date: 2024-11-08 DOI: 10.1002/prot.26760

Elliot Hill, Avery Hill, Elena Voisin, Amber Byrd, Allyn Schoeffler

{"title":"Localized Amino Acid Enrichment Analysis as a Tool for Understanding Protein Extremophilicity.","authors":"Elliot Hill, Avery Hill, Elena Voisin, Amber Byrd, Allyn Schoeffler","doi":"10.1002/prot.26760","DOIUrl":"10.1002/prot.26760","url":null,"abstract":"Sequence conservation analyses offer us a powerful glimpse of natural selection at work. Standard tools for measuring sequence conservation report conservation as a function of a specific location in a multiple sequence alignment and have proven indispensable in identifying highly constrained features such as active site residues. The advent of large-scale genomic sequencing efforts allows researchers to expand this paradigm and investigate more nuanced relationships between sequence and function. Here, we present a simple tool (SWiLoDD: Sliding Window Localized Differentiation Detection) that allows researchers to analyze local, rather than site-specific, conservation using a sliding window approach. Our tool accepts multiple sequence alignments partitioned based on a biological differentiator and returns alignment position-based, localized differential enrichment metrics for amino acids of choice. We present two case studies of this analysis in action: local-but-diffuse glycine enrichments in the ATPase subunits of thermophilic and psychrophilic bacterial gyrase homologs, and ligand- and interface-specific amino acid enrichments in halophilic bacterial crotonyl-CoA carboxylases/reductases. Though we have described examples of extremophilic bacterial proteins in this study, our tool may be used to investigate any set of homologous sequences from which sub-groups can be meaningfully partitioned. Our results suggest that investigating differential localized conservation in partitioned MSAs will expand our understanding of how sequence conservation and protein function are connected.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"702-715"},"PeriodicalIF":3.2,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606480","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}

引用次数: 0

Performance of Hybrid Strategies Combining MDockPP and AlphaFold2 in CAPRI Rounds 47-55. 结合MDockPP和AlphaFold2的混合策略在CAPRI回合47-55中的表现。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-02-04 DOI: 10.1002/prot.26805

Rui Duan, Xianjin Xu, Liming Qiu, Shuang Zhang, Xiaoqin Zou

引用次数: 0

DeepPhoPred: Accurate Deep Learning Model to Predict Microbial Phosphorylation. DeepPhoPred：预测微生物磷酸化的精确深度学习模型

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-02-01 Epub Date: 2024-09-06 DOI: 10.1002/prot.26734

Faisal Ahmed, Alok Sharma, Swakkhar Shatabda, Iman Dehzangi

{"title":"DeepPhoPred: Accurate Deep Learning Model to Predict Microbial Phosphorylation.","authors":"Faisal Ahmed, Alok Sharma, Swakkhar Shatabda, Iman Dehzangi","doi":"10.1002/prot.26734","DOIUrl":"10.1002/prot.26734","url":null,"abstract":"Phosphorylation is a substantial posttranslational modification of proteins that refers to adding a phosphate group to the amino acid side chain after translation process in the ribosome. It is vital to coordinate cellular functions, such as regulating metabolism, proliferation, apoptosis, subcellular trafficking, and other crucial physiological processes. Phosphorylation prediction in a microbial organism can assist in understanding pathogenesis and host-pathogen interaction, drug and antibody design, and antimicrobial agent development. Experimental methods for predicting phosphorylation sites are costly, slow, and tedious. Hence low-cost and high-speed computational approaches are highly desirable. This paper presents a new deep learning tool called DeepPhoPred for predicting microbial phospho-serine (pS), phospho-threonine (pT), and phospho-tyrosine (pY) sites. DeepPhoPred incorporates a two-headed convolutional neural network architecture with the squeeze and excitation blocks followed by fully connected layers that jointly learn significant features from the peptide's structural and evolutionary information to predict phosphorylation sites. Our empirical results demonstrate that DeepPhoPred significantly outperforms the existing microbial phosphorylation site predictors with its highly efficient deep-learning architecture. DeepPhoPred as a standalone predictor, all its source codes, and our employed datasets are publicly available at https://github.com/faisalahm3d/DeepPhoPred.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"465-481"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141867","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}

引用次数: 0

Physicochemical Evaluation of Remote Homology in the Twilight Zone. 暮光之城中远程同源物的物理化学评估。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-02-01 Epub Date: 2024-09-01 DOI: 10.1002/prot.26742

Jamie Dennis Dixson, Rajeev Kumar Azad

{"title":"Physicochemical Evaluation of Remote Homology in the Twilight Zone.","authors":"Jamie Dennis Dixson, Rajeev Kumar Azad","doi":"10.1002/prot.26742","DOIUrl":"10.1002/prot.26742","url":null,"abstract":"A fundamental problem in the field of protein evolutionary biology is determining the degree and nature of evolutionary relatedness among homologous proteins that have diverged to a point where they share less than 30% amino acid identity yet retain similar structures and/or functions. Such proteins are said to lie within the \"Twilight Zone\" of amino acid identity. Many researchers have leveraged experimentally determined structures in the quest to classify proteins in the Twilight Zone. Such endeavors can be highly time consuming and prohibitively expensive for large-scale analyses. Motivated by this problem, here we use molecular weight-hydrophobicity physicochemical dynamic time warping (MWHP DTW) to quantify similarity of simulated and real-world homologous protein domains. MWHP DTW is a physicochemical method requiring only the amino acid sequence to quantify similarity of related proteins and is particularly useful in determining similarity within the Twilight Zone due to its resilience to primary sequence substitution saturation. This is a step forward in determination of the relatedness among Twilight Zone proteins and most notably allows for the discrimination of random similarity and true homology in the 0%-20% identity range. This method was previously presented expeditiously just after the outbreak of COVID-19 because it was able to functionally cluster ACE2-binding betacoronavirus receptor binding domains (RBDs), a task that has been elusive using standard techniques. Here we show that one reason that MWHP DTW is an effective technique for comparisons within the Twilight Zone is because it can uncover hidden homology by exploiting physicochemical conservation, a problem that protein sequence alignment algorithms are inherently incapable of addressing within the Twilight Zone. Further, we present an extended definition of the Twilight Zone that incorporates the dynamic relationship between structural, physicochemical, and sequence-based metrics.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"452-464"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115478","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}

引用次数: 0

Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-95 Interactor (Cypin). 伐昔洛韦和阿昔洛韦是鸟嘌呤脱氨酶细胞质 PSD-95 互作因子 (Cypin) 的底物

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-02-01 Epub Date: 2024-08-29 DOI: 10.1002/prot.26740

Keith R Lange, Noor Rasheed, Xiaoyang Su, M Elena Diaz-Rubio, Bonnie L Firestein

{"title":"Valacyclovir and Acyclovir Are Substrates of the Guanine Deaminase Cytosolic PSD-95 Interactor (Cypin).","authors":"Keith R Lange, Noor Rasheed, Xiaoyang Su, M Elena Diaz-Rubio, Bonnie L Firestein","doi":"10.1002/prot.26740","DOIUrl":"10.1002/prot.26740","url":null,"abstract":"Valacyclovir, enzymatically hydrolyzed in the body to acyclovir, is a guanine-based nucleoside analog commonly prescribed as an antiviral therapy. Previous reports suggest that guanosine analogs bind to guanine deaminase; however, it is unclear whether they act as inhibitors or substrates. Data from our laboratory suggest that inhibition of guanine deaminase by small molecules attenuates spinal cord injury-induced neuropathic pain. Here, we examine whether the guanosine analogs valacyclovir and acyclovir are deaminated by cypin (cytosolic PSD-95 interactor), the major guanine deaminase in the body, or if they act as cypin inhibitors. Using purified Rattus norvegicus cypin, we use NADH-coupled assay to confirm deamination of valacyclovir and determined Michaelis-Menten constants. Subsequently, we use tryptophan fluorescence quenching assay to calculate dissociation constants for valacyclovir and acyclovir and find that inclusion of the valine motif in valacyclovir increases affinity for cypin compared to acyclovir. To our knowledge, neither K m nor K D values for cypin has been previously reported for either compound. We use Amplex Red assay and demonstrate that both valacyclovir and acyclovir are cypin substrates and that their metabolites are further processed by xanthine oxidase and uricase. Using molecular dynamics simulations, we demonstrate that an alpha helix near the active site is displaced when valacyclovir binds to cypin. Furthermore, we used LC-MS-based assay to directly confirm deamination of valacyclovir by cypin. Taken together, our results demonstrate a novel role for cypin in deamination of valacyclovir and acyclovir and suggest that therapeutics based on purine structures may be inactivated by cypin, decreasing inhibitory efficacy.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"430-440"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694556/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142115479","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}

引用次数: 0

Structural and Biochemical Characterization of Aminoglycoside Nucleotidyltransferase(6)-Ib From Campylobacter fetus subsp. fetus. 胎儿弯曲杆菌亚种氨基糖苷核苷酸转移酶（6）-Ib 的结构和生化特性分析

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2025-02-01 Epub Date: 2024-09-09 DOI: 10.1002/prot.26745

Pranav Nalam, Paul D Cook, Brian A Smith

{"title":"Structural and Biochemical Characterization of Aminoglycoside Nucleotidyltransferase(6)-Ib From Campylobacter fetus subsp. fetus.","authors":"Pranav Nalam, Paul D Cook, Brian A Smith","doi":"10.1002/prot.26745","DOIUrl":"10.1002/prot.26745","url":null,"abstract":"Aminoglycoside antibiotics have played a critical role in the treatment of both Gram-negative and Gram-positive bacterial infections. However, antibiotic resistance has severely compromised the efficacy of aminoglycosides. A leading cause of aminoglycoside resistance is mediated by bacterial enzymes that inactivate these drugs via chemical modification. Aminoglycoside nucleotidyltransferase-6 (ANT(6)) enzymes inactivate streptomycin by transferring an adenyl group from ATP to position 6 on the antibiotic. Despite the clinical significance of this activity, ANT(6) enzymes remain relatively uncharacterized. Here, we report the first high resolution x-ray crystallographic structure of ANT(6)-Ib from Campylobacter fetus subsp. fetus bound with streptomycin. Structural modeling and gel filtration chromatography experiments suggest that the enzyme exists as a dimer in which both subunits contribute to the active site. Moreover, superposition of the ANT(6)-Ib structure with the structurally related enzyme lincosamide nucleotidyltransferase B (LinB) permitted the identification of a putative nucleotide binding site. These data also suggest that residues D44 and D46 coordinate essential divalent metal ions and D102 functions as the catalytic base.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"413-419"},"PeriodicalIF":3.2,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142156778","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}

引用次数: 0