Proteins-Structure Function and Bioinformatics最新文献

GPCR Signaling: A Study of the Interplay Between Structure, Energy, and Function. GPCR 信号：结构、能量和功能之间相互作用的研究。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-08-02 DOI: 10.1002/prot.26724

Yann Chalopin

{"title":"GPCR Signaling: A Study of the Interplay Between Structure, Energy, and Function.","authors":"Yann Chalopin","doi":"10.1002/prot.26724","DOIUrl":"10.1002/prot.26724","url":null,"abstract":"G protein-coupled receptors (GPCRs) exemplify sophisticated allosteric communication, transducing extracellular signals through ligand-induced structural rearrangements that resonate through the molecular scaffold. Despite extensive study, the biophysical underpinnings of how conformational changes spread remain unclear. This work employs a novel physics-based framework to characterize the role of energy dissipation in directing intramolecular signaling pathways. By modeling each residue as a network of coupled oscillators, we generate a localization landscape depicting the vibrational energy distribution throughout the protein scaffold. Quantifying directional energy flux between residues reveals distinct pathways for energy and information transfer, illuminating sequences of allosteric communication. Our analysis of CB1 and CCR5 crystal structures unveils an anisotropic pattern of energy dissipation aligning with key functional dynamics, such as activation-related conformational changes. These anisotropic patterns of vibrational energy flow constitute pre-configured channels for allosteric signaling. Elucidating the relationship between structural topology and energy dissipation patterns provides key insights into the thermodynamic drivers of conformational signaling. This methodology significantly advances our mechanistic understanding of allostery in GPCRs and presents a broadly applicable approach for rationally dissecting allosteric communication pathways, with potential implications for structure-based drug design targeting these critical receptors.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141879917","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

Unveiling a Hidden Pocket in HIV-1 Protease: New Insights Into Retroviral Protease Cantilever-Tip Region Characteristics. 揭开 HIV-1 蛋白酶的隐藏口袋：逆转录病毒蛋白酶悬臂尖端区域特征的新见解

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-08-07 DOI: 10.1002/prot.26735

Dean Sherry, Yasien Sayed

{"title":"Unveiling a Hidden Pocket in HIV-1 Protease: New Insights Into Retroviral Protease Cantilever-Tip Region Characteristics.","authors":"Dean Sherry, Yasien Sayed","doi":"10.1002/prot.26735","DOIUrl":"10.1002/prot.26735","url":null,"abstract":"The HIV-1 protease is critical for the process of viral maturation and as such, it is one of the most well characterized proteins in the Protein Data Bank. There is some evidence to suggest that the HIV-1 protease is capable of accommodating small molecule fragments at several locations on its surface outside of the active site. However, some pockets on the surface of proteins remain unformed in the apo structure and are termed \"cryptic sites.\" To date, no cryptic sites have been identified in the structure of HIV-1 protease. Here, we characterize a novel cryptic cantilever pocket on the surface of the HIV-1 protease through mixed-solvent molecular dynamics simulations using several probes. Interestingly, we noted that several homologous retroviral proteases exhibit evolutionarily conserved dynamics in the cantilever region and possess a conserved pocket in the cantilever region. Immobilization of the cantilever region of the HIV-1 protease via disulfide cross-linking resulted in curling-in of the flap tips and the propensity for the protease to adopt a semi-open flap conformation. Structure-based analysis and fragment-based screening of the cryptic cantilever pocket suggested that the pocket may be capable of accommodating ligand structures. Furthermore, molecular dynamics simulations of a top scoring fragment bound to the cryptic pocket illustrated altered flap dynamics of the fragment-bound enzyme. Together, these results suggest that the mobility of the cantilever region plays a key role in the global dynamics of retroviral proteases. Therefore, the cryptic cantilever pocket of the HIV-1 protease may represent an interesting target for future in vitro studies.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141898996","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

Structural Classification Insights Into the Plant Defensive Peptides. 植物防御肽的结构分类见解

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-08-20 DOI: 10.1002/prot.26736

Inda Setyawati, Ahmad Fadhlullah Husaini, Aprijal Ghiyas Setiawan, I Made Artika, Laksmi Ambarsari, Waras Nurcholis, Keni Vidilaseris, Popi Asri Kurniatin

引用次数: 0

Hereditary Amyloidosis: Insights Into a Fibrinogen A Variant Protein. 遗传性淀粉样变性：对纤维蛋白原 A 变异蛋白的认识

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-07-19 DOI: 10.1002/prot.26732

Elizabeth R Cattaneo, Romina A Gisonno, Martín C Abba, Marianela Santana, Silvana A Rosú, Elsa Nucifora, María A Aguirre, María C Giordani, M Alejandra Tricerri, Nahuel A Ramella

{"title":"Hereditary Amyloidosis: Insights Into a Fibrinogen A Variant Protein.","authors":"Elizabeth R Cattaneo, Romina A Gisonno, Martín C Abba, Marianela Santana, Silvana A Rosú, Elsa Nucifora, María A Aguirre, María C Giordani, M Alejandra Tricerri, Nahuel A Ramella","doi":"10.1002/prot.26732","DOIUrl":"10.1002/prot.26732","url":null,"abstract":"Amyloidosis are a group of diseases in which soluble proteins aggregate and deposit in fibrillar conformation extracellularly in tissues. The effectiveness of therapeutic strategies depends on the specific protein involved, being crucial to accurately determine its nature. Moreover, following the diagnosis, the search for the mutation within relatives allows the clinical advice. Here we report the precise diagnosis and explored the possible reasons of the structural pathogenicity for a renal amyloidosis related to a fibrinogen Aα-chain variant. Whole-exome sequencing and GATK calling pipeline were leveraged to characterize the protein variant present in a patient with kidney failure. Bioinformatics strategies were applied to suggest potential explanations of the variants aggregation. Our pipeline allowed the identification of a single-point variant of fibrinogen Aα-chain, which opened the possibility of curative transplantation. In silico structural analysis suggested that the pathogenicity of the variant may be attributed to a heightened susceptibility to yield a peptide prone to deposit as an oligomer with a β-sheet structure. Exploiting the comprehensive coverage of whole-genome sequencing, we managed to fill a vacant stage in the diagnosis of hereditary amyloidosis and to stimulate the advancement in biomedicine.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731673","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

Mutagenesis Supports AlphaFold Prediction of How Modular Polyketide Synthase Acyl Carrier Proteins Dock With Downstream Ketosynthases. 突变支持对模块化多酮类合成酶酰基载体蛋白如何与下游酮合成酶对接的 AlphaFold 预测。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-07-30 DOI: 10.1002/prot.26733

Melissa Hirsch, Ronak R Desai, Shreyas Annaswamy, Adrian T Keatinge-Clay

{"title":"Mutagenesis Supports AlphaFold Prediction of How Modular Polyketide Synthase Acyl Carrier Proteins Dock With Downstream Ketosynthases.","authors":"Melissa Hirsch, Ronak R Desai, Shreyas Annaswamy, Adrian T Keatinge-Clay","doi":"10.1002/prot.26733","DOIUrl":"10.1002/prot.26733","url":null,"abstract":"The docking of an acyl carrier protein (ACP) domain with a downstream ketosynthase (KS) domain in each module of a polyketide synthase (PKS) helps ensure accurate biosynthesis. If the polyketide chain bound to the ACP has been properly modified by upstream processing enzymes and is compatible with gatekeeping residues in the KS tunnel, a transacylation reaction can transfer it from the 18.1-Å phosphopantetheinyl arm of the ACP to the reactive cysteine of the KS. AlphaFold-Multimer predicts a general interface for these transacylation checkpoints. Half of the solutions obtained for 50 ACP/KS pairs show the KS motif TxLGDP forming the first turn of an α-helix, as in reported structures, while half show it forming a type I β-turn not previously observed. Solutions with the latter conformation may represent how these domains are relatively positioned during the transacylation reaction, as the entrance to the KS active site is relatively open and the phosphopantetheinylated ACP serine and the reactive KS cysteine are relatively closer-17.2 versus 20.9 Å, on average. To probe the predicted interface, 20 mutations were made to KS surface residues within the model triketide lactone synthase P1-P6-P7. The activities of these mutants are consistent with the proposed interface.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11543512/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794176","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 Analysis of Butanol Dehydrogenase From Thermotoga maritima. 海洋嗜热菌丁醇脱氢酶的结构和生化分析

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-07-18 DOI: 10.1002/prot.26731

Xue Bai, Ke Xu, Zhidan Zhao, Huiwen Qin, Ki Hyun Nam, Chunshan Quan, Nam-Chul Ha, Yongbin Xu

{"title":"Structural and Biochemical Analysis of Butanol Dehydrogenase From Thermotoga maritima.","authors":"Xue Bai, Ke Xu, Zhidan Zhao, Huiwen Qin, Ki Hyun Nam, Chunshan Quan, Nam-Chul Ha, Yongbin Xu","doi":"10.1002/prot.26731","DOIUrl":"10.1002/prot.26731","url":null,"abstract":"Butanol dehydrogenase (BDH) plays a crucial role in butanol biosynthesis by catalyzing the conversion of butanal to butanol using the coenzyme NAD(P)H. In this study, we observed that BDH from Thermotoga maritima (TmBDH) exhibits dual coenzyme specificity and catalytic activity with NADPH as the coenzyme under highly alkaline conditions. Additionally, a thermal stability analysis on TmBDH demonstrated its excellent activity retention even at elevated temperatures of 80°C. These findings demonstrate the superior thermal stability of TmBDH and suggest that it is a promising candidate for large-scale industrial butanol production. Furthermore, we discovered that TmBDH effectively catalyzes the conversion of aldehydes to alcohols and exhibits a wide range of substrate specificities toward aldehydes, while excluding alcohols. The dimeric state of TmBDH was observed using rapid online buffer exchange native mass spectrometry. Additionally, we analyzed the coenzyme-binding sites and inferred the possible locations of the substrate-binding sites. These results provide insights that improve our understanding of BDHs.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635973","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

luxA Gene From Enhygromyxa salina Encodes a Functional Homodimeric Luciferase. 盐沼藻的 luxA 基因编码一种功能性同源二聚体荧光素酶。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-08-22 DOI: 10.1002/prot.26739

Anna Yudenko, Sergey V Bazhenov, Vladimir A Aleksenko, Ivan M Goncharov, Oleg Semenov, Alina Remeeva, Vera V Nazarenko, Elizaveta Kuznetsova, Vadim V Fomin, Maria N Konopleva, Rahaf Al Ebrahim, Nikolai N Sluchanko, Yury Ryzhykau, Yury S Semenov, Alexander Kuklin, Ilya V Manukhov, Ivan Gushchin

{"title":"luxA Gene From Enhygromyxa salina Encodes a Functional Homodimeric Luciferase.","authors":"Anna Yudenko, Sergey V Bazhenov, Vladimir A Aleksenko, Ivan M Goncharov, Oleg Semenov, Alina Remeeva, Vera V Nazarenko, Elizaveta Kuznetsova, Vadim V Fomin, Maria N Konopleva, Rahaf Al Ebrahim, Nikolai N Sluchanko, Yury Ryzhykau, Yury S Semenov, Alexander Kuklin, Ilya V Manukhov, Ivan Gushchin","doi":"10.1002/prot.26739","DOIUrl":"10.1002/prot.26739","url":null,"abstract":"Several clades of luminescent bacteria are known currently. They all contain similar lux operons, which include the genes luxA and luxB encoding a heterodimeric luciferase. The aldehyde oxygenation reaction is presumed to be catalyzed primarily by the subunit LuxA, whereas LuxB is required for efficiency and stability of the complex. Recently, genomic analysis identified a subset of bacterial species with rearranged lux operons lacking luxB. Here, we show that the product of the luxA gene from the reduced luxACDE operon of Enhygromyxa salina is luminescent upon addition of aldehydes both in vivo in Escherichia coli and in vitro. Overall, EsLuxA is much less bright compared with luciferases from Aliivibrio fischeri (AfLuxAB) and Photorhabdus luminescens (PlLuxAB), and most active with medium-chain C4-C9 aldehydes. Crystal structure of EsLuxA determined at the resolution of 2.71 Å reveals a (β/α)8 TIM-barrel fold, characteristic for other bacterial luciferases, and the protein preferentially forms a dimer in solution. The mobile loop residues 264-293, which form a β-hairpin or a coil in Vibrio harveyi LuxA, form α-helices in EsLuxA. Phylogenetic analysis shows EsLuxA and related proteins may be bacterial protoluciferases that arose prior to duplication of the luxA gene and its speciation to luxA and luxB in the previously described luminescent bacteria. Our work paves the way for the development of new bacterial luciferases that have an advantage of being encoded by a single gene.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019712","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

Order/Disorder Transitions Upon Protein Binding: A Unifying Perspective. 蛋白质结合时的有序/无序转变：统一的视角

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-08-19 DOI: 10.1002/prot.26737

Olga O Lebedenko, Ashok Sekhar, Nikolai R Skrynnikov

引用次数: 0

Mechanistic Insight Into the Conformational Changes of Cas8 Upon Binding to Different PAM Sequences in the Transposon-Encoded Type I-F CRISPR-Cas System. 转座子编码的 I-F 型 CRISPR-Cas 系统中 Cas8 与不同 PAM 序列结合时的构象变化的机理洞察。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-12-01 Epub Date: 2024-08-22 DOI: 10.1002/prot.26730

Amnah Alalmaie, Raed Khashan

{"title":"Mechanistic Insight Into the Conformational Changes of Cas8 Upon Binding to Different PAM Sequences in the Transposon-Encoded Type I-F CRISPR-Cas System.","authors":"Amnah Alalmaie, Raed Khashan","doi":"10.1002/prot.26730","DOIUrl":"10.1002/prot.26730","url":null,"abstract":"The INTEGRATE system is a gene-editing approach that offers advantages over the widely used CRISPR-Cas9 system. It does not introduce double strand breaks in the target DNA but rather integrates the desired DNA sequence directly into it. The first step in the integration process is PAM recognition, which is critical to understanding and optimizing the system. Experimental testing revealed varying integration efficiencies of different PAM mutants, and computational simulations were carried out to gain mechanistic insight into the conformational changes of Cas8 during PAM recognition. Our results showed that the interaction between Arg246 and guanine at position (-1) of the target strand is critical for PAM recognition. We found that unfavorable interactions in the 5'-AC-3' PAM mutant disrupted this interaction and may be responsible for its 0% integration efficiency. Additionally, we discovered that PAM sequences not only initiate the integration process but also regulate it through an allosteric mechanism that connects the N-terminal domain and the helical bundle of Cas8. This allosteric regulation was present in all PAMs tested, even those with lower integration efficiencies, such as 5'-TC-3' and 5'-AC-3'. We identified the Cas8 residues that are involved in this regulation. Our findings provide valuable insights into PAM recognition mechanisms in the INTEGRATE system and can help improve the gene-editing technology.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019713","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

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 : 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":"https://doi.org/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":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-11-08","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