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

L858R/L718Q and L858R/L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen Bonds. 表皮生长因子受体 L858R/L718Q 和 L858R/L792H 突变通过形成额外的氢键诱导对奥希替尼的耐药性

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-04 DOI: 10.1002/prot.26761

Ibrahim A Imam, Shatha Al Adawi, Xiaoqi Liu, Sally Ellingson, Christine F Brainson, Hunter N B Moseley, Ralph Zinner, Shulin Zhang, Qing Shao

{"title":"L858R/L718Q and L858R/L792H Mutations of EGFR Inducing Resistance Against Osimertinib by Forming Additional Hydrogen Bonds.","authors":"Ibrahim A Imam, Shatha Al Adawi, Xiaoqi Liu, Sally Ellingson, Christine F Brainson, Hunter N B Moseley, Ralph Zinner, Shulin Zhang, Qing Shao","doi":"10.1002/prot.26761","DOIUrl":"https://doi.org/10.1002/prot.26761","url":null,"abstract":"Acquired resistance to first-line treatments in various cancers both promotes cancer recurrence as well as limits effective treatment. This is true for epidermal growth factor receptor (EGFR) mutations, for which secondary EGFR mutations are one of the principal mechanisms conferring resistance to the covalent inhibitor osimertinib. Thus, it is very important to develop a deeper understanding of the secondary mutational resistance mechanisms associated with EGFR mutations arising in tumors treated with osimertinib to expedite the development of innovative therapeutic drugs to overcome acquired resistance. This work uses all-atom molecular dynamics (MD) simulations to investigate the conformational variation of two reported EGFR mutants (L858R/L718Q and L858R/L792H) that resist osimertinib. The wild-type EGFR kinase domain and the L858R mutant are used as the reference. Our MD simulation results revealed that both the L718Q and L792H secondary mutations induce additional hydrogen bonds between the residues in the active pocket and the residues with the water molecules. These additional hydrogen bonds reduce the exposure area of C797, the covalent binding target of osimertinib. The additional hydrogen bonds also influence the binding affinity of the EGFR kinase domain by altering the secondary structure and flexibility of the amino acid residues in the domain. Our work highlights how the two reported mutations may alter both residue-residue and residue-solvent hydrogen bonds, affecting protein binding properties, which could be helpful for future drug discovery.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142570153","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

Multiple Functional Protein-Protein Interaction Interfaces Allosterically Regulate ATP-Binding in Cyclin-Dependent Kinase-1. 多种功能性蛋白质-蛋白质相互作用界面异构调节 Cyclin-Dependent Kinase-1 的 ATP 结合。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-07-16 DOI: 10.1002/prot.26729

Krishna Kant Vishwakarma, Ullas Seetharam Kolthur, Ravindra Venkatramani

{"title":"Multiple Functional Protein-Protein Interaction Interfaces Allosterically Regulate ATP-Binding in Cyclin-Dependent Kinase-1.","authors":"Krishna Kant Vishwakarma, Ullas Seetharam Kolthur, Ravindra Venkatramani","doi":"10.1002/prot.26729","DOIUrl":"10.1002/prot.26729","url":null,"abstract":"The ATP-dependent phosphorylation activity of cyclin-dependent kinase 1 (CDK1), an essential enzyme for cell cycle progression, is regulated by interactions with Cyclin-B, substrate, and Cks proteins. We have recently shown that active site acetylation in CDK1 abrogated binding to Cyclin-B which posits an intriguing long-range communication between the catalytic site and the protein-protein interaction (PPI) interface. Now, we demonstrate a general allosteric link between the CDK1 active site and all three of its PPI interfaces through atomistic molecular dynamics (MD) simulations. Specifically, we examined ATP binding free energies to CDK1 in native nonacetylated (K33wt) and acetylated (K33Ac) forms as well as the acetyl-mimic K33Q and the acetyl-null K33R mutant forms, which are accessible in vitro. In agreement with experiments, ATP binding is stronger in K33wt relative to the other three perturbed states. Free energy decomposition reveals, in addition to expected local changes, significant and selective nonlocal entropic responses to ATP binding/perturbation of K33 from the <math> <semantics><mrow><mi>αC</mi></mrow> </semantics> </math> -helix, activation loop (A-loop), and <math> <semantics><mrow><mi>αG</mi></mrow> </semantics> </math> - <math> <semantics><mrow><mi>α</mi></mrow> </semantics> </math> H segments in CDK1 which interface with Cyclin-B, substrate, and Cks proteins, respectively. Statistical analysis reveals that while entropic responses of protein segments to active site perturbations are on average correlated with their dynamical changes, such correlations are lost in about 9%-48% of the dataset depending on the segment. Besides proving the bi-directional communication between the active site and the CDK1:Cyclin-B interface, our study uncovers a hitherto unknown mode of ATP binding regulation by multiple PPI interfaces in CDK1.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1329-1342"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141621819","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

Molecular Basis of MC1R Activation: Mutation-Induced Alterations in Structural Dynamics. MC1R 激活的分子基础：突变诱导的结构动力学变化。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-06-25 DOI: 10.1002/prot.26722

Fernando Guimarães Cavatão, Éderson Sales Moreira Pinto, Mathias J Krause, Clarice Sampaio Alho, Marcio Dorn

{"title":"Molecular Basis of MC1R Activation: Mutation-Induced Alterations in Structural Dynamics.","authors":"Fernando Guimarães Cavatão, Éderson Sales Moreira Pinto, Mathias J Krause, Clarice Sampaio Alho, Marcio Dorn","doi":"10.1002/prot.26722","DOIUrl":"10.1002/prot.26722","url":null,"abstract":"The MC1R protein is a receptor found in melanocytes that plays a role in melanin synthesis. Mutations in this protein can impact hair color, skin tone, tanning ability, and increase the risk of skin cancer. The MC1R protein is activated by the alpha-melanocyte-stimulating hormone (α-MSH). Previous studies have shown that mutations affect the interaction between MC1R and α-MSH; however, the mechanism behind this process is poorly understood. Our study aims to shed light on this mechanism using molecular dynamics (MD) simulations to analyze the Asp84Glu and Asp294His variants. We simulated both the wild-type (WT) protein and the mutants with and without ligand. Our results reveal that mutations induce unique conformations during state transitions, hindering the switch between active and inactive states and decreasing cellular levels of cAMP. Interestingly, Asp294His showed increased ligand affinity but decreased protein activity, highlighting that tighter binding does not always lead to increased activation. Our study provides insights into the molecular mechanisms underlying the impact of MC1R mutations on protein activity.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1297-1307"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461101","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

Protein-Protein Interaction Prediction via Structure-Based Deep Learning. 通过基于结构的深度学习进行蛋白质-蛋白质相互作用预测。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-06-23 DOI: 10.1002/prot.26721

Yucong Liu, Yijun Liu, Zhenhai Li

引用次数: 0

Conformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies. Alsin MORN 单体和二聚体组装的构象动力学和分子特征。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-07-18 DOI: 10.1002/prot.26728

Marcello Miceli, Marco Cannariato, Riccardo Tortarolo, Lorenzo Pallante, Eric A Zizzi, Marco A Deriu

{"title":"Conformational Dynamics and Molecular Characterization of Alsin MORN Monomer and Dimeric Assemblies.","authors":"Marcello Miceli, Marco Cannariato, Riccardo Tortarolo, Lorenzo Pallante, Eric A Zizzi, Marco A Deriu","doi":"10.1002/prot.26728","DOIUrl":"10.1002/prot.26728","url":null,"abstract":"Despite the ubiquity of membrane occupation recognition nexus (MORN) motifs across diverse species in both eukaryotic and prokaryotic organisms, these protein domains remain poorly characterized. Their significance is underscored in the context of the Alsin protein, implicated in the debilitating condition known as infantile-onset ascending hereditary spastic paralysis (IAHSP). Recent investigations have proposed that mutations within the Alsin MORN domain disrupt proper protein assembly, precluding the formation of the requisite tetrameric configuration essential for the protein's inherent biological activity. However, a comprehensive understanding of the relationship between the biological functions of Alsin and its three-dimensional molecular structure is hindered by the lack of available experimental structures. In this study, we employed and compared several protein structure prediction algorithms to identify a three-dimensional structure for the putative MORN of Alsin. Furthermore, inspired by experimental pieces of evidence from previous studies, we employed the developed models to predict and investigate two homo-dimeric assemblies, characterizing their stability. This study's insights into the three-dimensional structure of the Alsin MORN domain and the stability dynamics of its homo-dimeric assemblies suggest an antiparallel linear configuration stabilized by a noncovalent interaction network.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1343-1353"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635972","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

Exploring ligands that target von Willebrand factor selectively under oxidizing conditions through docking and molecular dynamics simulations. 通过对接和分子动力学模拟，探索在氧化条件下选择性靶向 von Willebrand 因子的配体。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-06-03 DOI: 10.1002/prot.26706

Gianluca Interlandi

{"title":"Exploring ligands that target von Willebrand factor selectively under oxidizing conditions through docking and molecular dynamics simulations.","authors":"Gianluca Interlandi","doi":"10.1002/prot.26706","DOIUrl":"10.1002/prot.26706","url":null,"abstract":"The blood protein von Willebrand factor (VWF) is a large multimeric protein that, when activated, binds to blood platelets, tethering them to the site of vascular injury and initiating blood coagulation. This process is critical for the normal hemostatic response, but especially under inflammatory conditions, it is thought to be a major player in pathological thrombus formation. For this reason, VWF has been the target for the development of anti-thrombotic therapeutics. However, it is challenging to prevent pathological thrombus formation while still allowing normal physiological blood coagulation, as currently available anti-thrombotic therapeutics are known to cause unwanted bleeding, in particular intracranial hemorrhage. This work explores the possibility of inhibiting VWF selectively under the inflammatory conditions present during pathological thrombus formation. In particular, the A2 domain of VWF is known to inhibit the neighboring A1 domain from binding to the platelet surface receptor GpIbα, and this auto-inhibitory mechanism has been shown to be removed by oxidizing agents released during inflammation. Hence, finding drug molecules that bind at the interface between A1 and A2 only under oxidizing conditions could restore such an auto-inhibitory mechanism. Here, by using a combination of computational docking, molecular dynamics simulations, and free energy perturbation calculations, a ligand from the ZINC15 database was identified that binds at the A1A2 interface, with the interaction being stronger under oxidizing conditions. The results provide a framework for the discovery of drug molecules that bind to a protein selectively in the presence of inflammatory conditions.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1261-1275"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471382/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141201366","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

A Closer Look at Type I Left-Handed β-Helices Provides a Better Understanding in Their Sequence-Structure Relationship: Toward Their Rational Design. 仔细观察 I 型左手β-elices 更好地理解了它们的序列-结构关系：实现合理设计。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-07-09 DOI: 10.1002/prot.26726

Maxime Naudé, Peter Faller, Vincent Lebrun

引用次数: 0

Phosphorylation Mechanism Switching in Histidine Kinases Is a Tool for Fast Protein Evolution: Insights From AlphaFold Models. 组氨酸激酶的磷酸化机制转换是蛋白质快速进化的工具：阿尔法折叠模型的启示。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-06-17 DOI: 10.1002/prot.26708

Federico A Olivieri, Marcelo A Marti, Diana E Wetzler

{"title":"Phosphorylation Mechanism Switching in Histidine Kinases Is a Tool for Fast Protein Evolution: Insights From AlphaFold Models.","authors":"Federico A Olivieri, Marcelo A Marti, Diana E Wetzler","doi":"10.1002/prot.26708","DOIUrl":"10.1002/prot.26708","url":null,"abstract":"Histidine kinases (HKs) are a central part of bacterial environmental-sensing two-component systems. They provide their hosts with the ability to respond to a wide range of physical and chemical signals. HKs are multidomain proteins consisting of at least a sensor domain, dimerization and phosphorylation domain (DHp), and a catalytic domain. They work as homodimers and the existence of two different autophosphorylation mechanisms (cis and trans) has been proposed as relevant for pathway specificity. Although several HKs have been intensively studied, a precise sequence-to-structure explanation of why and how either cis or trans phosphorylation occurs is still unavailable nor is there any evolutionary analysis on the subject. In this work, we show that AlphaFold can accurately determine whether an HK dimerizes in a cis or trans structure. By modeling multiple HKs we show that both cis- and trans-acting HKs are common in nature and the switch between mechanisms has happened multiple times in the evolutionary history of the family. We then use AlphaFold modeling to explore the molecular determinants of the phosphorylation mechanism. We conclude that it is the difference in lengths of the helices surrounding the DHp loop that determines the mechanism. We also show that very small changes in these helices can cause a mechanism switch. Despite this, previous evidence shows that for a particular HK the phosphorylation mechanism is conserved. This suggests that the phosphorylation mechanism participates in system specificity and mechanism switching provides these systems with a way to diverge.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1276-1286"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141332611","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

A Biochemical and Biophysical Analysis of the Interaction of nsp9 with nsp12 from SARS-CoV-2-Implications for Future Drug Discovery Efforts. 来自 SARS-CoV-2 的 nsp9 与 nsp12 相互作用的生化和生物物理分析--对未来药物发现工作的启示。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-11-01 Epub Date: 2024-07-03 DOI: 10.1002/prot.26725

David L Baker, Bing Wang, Lorna E Wilkinson-White, Serene El-Kamand, Thomas A Allport, Sandro F Ataide, Ann H Kwan, Irina Artsimovitch, Liza Cubeddu, Roland Gamsjaeger

{"title":"A Biochemical and Biophysical Analysis of the Interaction of nsp9 with nsp12 from SARS-CoV-2-Implications for Future Drug Discovery Efforts.","authors":"David L Baker, Bing Wang, Lorna E Wilkinson-White, Serene El-Kamand, Thomas A Allport, Sandro F Ataide, Ann H Kwan, Irina Artsimovitch, Liza Cubeddu, Roland Gamsjaeger","doi":"10.1002/prot.26725","DOIUrl":"10.1002/prot.26725","url":null,"abstract":"The ongoing global pandemic of the coronavirus 2019 (COVID-19) disease is caused by the virus SARS-CoV-2, with very few highly effective antiviral treatments currently available. The machinery responsible for the replication and transcription of viral RNA during infection is made up of several important proteins. Two of these are nsp12, the catalytic subunit of the viral polymerase, and nsp9, a cofactor of nsp12 involved in the capping and priming of viral RNA. While several recent studies have determined the structural details of the interaction of nsp9 with nsp12 in the context of RNA capping, very few biochemical or biophysical details are currently available. In this study, we have used a combination of surface plasmon resonance (SPR) experiments, size exclusion chromatography (SEC) experiments, and biochemical assays to identify specific nsp9 residues that are critical for nsp12 binding as well as RNAylation, both of which are essential for the RNA capping process. Our data indicate that nsp9 dimerization is unlikely to play a significant functional role in the virus. We confirm that a set of recently discovered antiviral peptides inhibit nsp9-nsp12 interaction by specifically binding to nsp9; however, we find that these peptides do not impact RNAylation. In summary, our results have important implications for future drug discovery efforts to combat SARS-CoV-2 and any newly emerging coronaviruses.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":"1308-1317"},"PeriodicalIF":3.2,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11471385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494429","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

Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding. 选择性抑制 hsp90 Paralogs：揭示螺旋 1 在 Grp94 选择性配体结合中的作用

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-10-29 DOI: 10.1002/prot.26756

Nanette L S Que, Paul M Seidler, Wen J Aw, Gabriela Chiosis, Daniel T Gewirth

{"title":"Selective Inhibition of hsp90 Paralogs: Uncovering the Role of Helix 1 in Grp94-Selective Ligand Binding.","authors":"Nanette L S Que, Paul M Seidler, Wen J Aw, Gabriela Chiosis, Daniel T Gewirth","doi":"10.1002/prot.26756","DOIUrl":"10.1002/prot.26756","url":null,"abstract":"Grp94 is the endoplasmic reticulum paralog of the hsp90 family of chaperones, which have been targeted for therapeutic intervention via their highly conserved ATP binding sites. The design of paralog-selective inhibitors relies on understanding the protein structural elements that drive higher affinity in selective inhibitors. Here, we determined the structures of Grp94 and Hsp90 in complex with the Grp94-selective inhibitor PU-H36, and of Grp94 with the non-selective inhibitor PU-H71. In Grp94, PU-H36 derives its higher affinity by utilizing Site 2, a Grp94-specific side pocket adjoining the ATP binding cavity, but in Hsp90 PU-H36 occupies Site 1, a side pocket that is accessible in all paralogs with which it makes lower affinity interactions. The structure of Grp94 in complex with PU-H71 shows only Site 1 binding. While changes in the conformation of helices 4 and 5 in the N-terminal domain occur when ligands bind to Site 1 of both Hsp90 and Grp94, large conformational shifts that also involve helix 1 are associated with the engagement of the Site 2 pocket in Grp94 only. Site 2 in Hsp90 is blocked and its helix 1 conformation is insensitive to ligand binding. To understand the role of helix 1 in ligand selectivity, we tested the binding of PU-H36 and other Grp94-selective ligands to chimeric Grp94/Hsp90 constructs. These studies show that helix 1 is the major determinant of selectivity for Site 2 targeted ligands and also influences the rate of ATPase activity in Hsp90 paralogs.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":" ","pages":""},"PeriodicalIF":3.2,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142549199","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