Proteins-Structure Function and Bioinformatics最新文献_第3页

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":null,"pages":null},"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

PIM-1L Kinase Binds to and Inactivates SRPK1: A Biochemical and Molecular Dynamics Study. PIM-1L 激酶与 SRPK1 结合并使其失活：一项生物化学和分子动力学研究。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-10-27 DOI: 10.1002/prot.26757

Nastazia Lesgidou, Anastasia Koukiali, Eleni Nikolakaki, Thomas Giannakouros, Metaxia Vlassi

{"title":"PIM-1L Kinase Binds to and Inactivates SRPK1: A Biochemical and Molecular Dynamics Study.","authors":"Nastazia Lesgidou, Anastasia Koukiali, Eleni Nikolakaki, Thomas Giannakouros, Metaxia Vlassi","doi":"10.1002/prot.26757","DOIUrl":"https://doi.org/10.1002/prot.26757","url":null,"abstract":"SR/RS dipeptide repeats vary in both length and position, and are phosphorylated by SR protein kinases (SRPKs). PIM-1L, the long isoform of PIM-1 kinase, the splicing of which has been implicated in acute myeloid leukemia, contains a domain that consists largely of repeating SR/RS and SH/HS dipeptides (SR/SH-rich). In order to extend our knowledge on the specificity and cellular functions of SRPK1, here we investigate whether PIM-1L could act as substrate of SRPK1 by a combination of biochemical and computational approaches. Our biochemical data showed that the SR/SH-rich domain of PIM-1L was able to associate with SRPK1, yet it could not act as a substrate but, instead, inactivated the kinase. In line with our biochemical data, molecular modeling followed by a microsecond-scale all-atom molecular dynamics (MD) simulation suggests that the SR/SH-rich domain acts as a pseudo-docking peptide that binds to the same acidic docking-groove used in other SRPK1 interactions and induces inactive SRPK1 conformations. Comparative community network analysis of the MD trajectories, unraveled the dynamic architecture of apo SRPK1 and notable alterations of allosteric communications upon PIM-1L peptide binding. This analysis also allowed us to identify key SRPK1 residues, including unique ones, with a pivotal role in mediating allosteric signal propagation within the kinase core. Interestingly, most of the identified amino acids correspond to cancer-associated amino acid changes, validating our results. In total, this work provides insights not only on the details of SRPK1 inhibition by the PIM-1L SR/SH-domain, but also contributes to an in-depth understanding of SRPK1 regulation.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142513837","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 : 2024-10-22 DOI: 10.1002/prot.26758

Xu Xia, Chenqiang Du, Yang Wang, Gaojie Song

引用次数: 0

Impact of N-Terminal Domain Conformation and Domain Interactions on RfaH Fold Switching. N 端结构域构象和结构域相互作用对 RfaH 折叠转换的影响

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-10-14 DOI: 10.1002/prot.26755

Bahman Seifi, Stefan Wallin

{"title":"Impact of N-Terminal Domain Conformation and Domain Interactions on RfaH Fold Switching.","authors":"Bahman Seifi, Stefan Wallin","doi":"10.1002/prot.26755","DOIUrl":"https://doi.org/10.1002/prot.26755","url":null,"abstract":"RfaH is a two-domain metamorphic protein involved in transcription regulation and translation initiation. To carry out its dual functions, RfaH relies on two coupled structural changes: Domain dissociation and fold switching. In the free state, the C-terminal domain (CTD) of RfaH adopts an all-α fold and is tightly associated with the N-terminal domain (NTD). Upon binding to RNA polymerase (RNAP), the domains dissociate and the CTD transforms into an all-β fold while the NTD remains largely, but not entirely, unchanged. We test the idea that a change in the conformation of an extended β-hairpin (β3-β4) located on the NTD, helps trigger domain dissociation. To this end, we use homology modeling to construct a structure, H1, which is similar to free RfaH but with a remodeled β3-β4 hairpin. We then use an all-atom physics-based model enhanced with a dual basin structure-based potential to simulate domain separation driven by the thermal unfolding of the CTD with NTD in a fixed, folded conformation. We apply our model to both free RfaH and H1. For H1 we find, in line with our hypothesis, that the CTD exhibits lower stability and the domains dissociate at a lower temperature T, as compared to free RfaH. We do not, however, observe complete refolding to the all-β state in these simulations, suggesting that a change in β3-β4 orientation aids in, but is not sufficient for, domain dissociation. In addition, we study the reverse fold switch in which RfaH returns from a domain-open all-β state to its domain-closed all-α state. We observe a T-dependent transition rate; fold switching is slow at low T, where the CTD tends to be kinetically trapped in its all-β state, and at high-T, where the all-α state becomes unstable. Consequently, our simulations suggest an optimal T at which fold switching is most rapid. At this T, the stabilities of both folds are reduced. Overall, our study suggests that both inter-domain interactions and conformational changes within NTD may be important for the proper functioning of RfaH.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142482016","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

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-10-11 DOI: 10.1002/prot.26753

Peter Røgen

{"title":"Sequence-Similar Protein Domain Pairs With Structural or Topological Dissimilarity.","authors":"Peter Røgen","doi":"10.1002/prot.26753","DOIUrl":"https://doi.org/10.1002/prot.26753","url":null,"abstract":"For a variety of applications, protein structures are clustered by sequence similarity, and sequence-redundant structures are disregarded. Sequence-similar chains are likely to have similar structures, but significant structural variation, as measured with RMSD, has been documented for sequence-similar chains and found usually to have a functional explanation. Moving two neighboring stretches of backbone through each other may change the chain topology and alter possible folding paths. The size of this motion is compatible to a variation in a flexible loop. We search and find domains with alternate chain topology in CATH4.2 sequence families relatively independent of sequence identity and of structural similarity as measured by RMSD. Structural, topological, and functional representative sets should therefore keep sequence-similar domains not just with structural variation but also with topological variation. We present BCAlign that finds Alignment and superposition of protein Backbone Curves by optimizing a user chosen convex combination of structural derivation and derivation between the structure-based sequence alignment and an input sequence alignment. Steric and topological obstructions from deforming a curve into an aligned curve are then found by a previously developed algorithm. For highly sequence-similar domains, sequence-based structural alignment better represents the chains motion and generally reveals larger structural and topological variation than structure-based does. Fold-switching protein pairs have been reported to be most frequent between X-ray and NMR structures and estimated to be underrepresented in the PDB as the alternate configuration is harder to resolve. Here we similarly find chain topology most frequently altered between X-ray and NMR structures.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142402131","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 : 2024-10-11 DOI: 10.1002/prot.26754

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

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 : 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":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-04","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

Invariant point message passing for protein side chain packing. 蛋白质侧链包装的不变点信息传递

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-10-01 Epub Date: 2024-05-24 DOI: 10.1002/prot.26705

Nicholas Z Randolph, Brian Kuhlman

{"title":"Invariant point message passing for protein side chain packing.","authors":"Nicholas Z Randolph, Brian Kuhlman","doi":"10.1002/prot.26705","DOIUrl":"10.1002/prot.26705","url":null,"abstract":"Protein side chain packing (PSCP) is a fundamental problem in the field of protein engineering, as high-confidence and low-energy conformations of amino acid side chains are crucial for understanding (and designing) protein folding, protein-protein interactions, and protein-ligand interactions. Traditional PSCP methods (such as the Rosetta Packer) often rely on a library of discrete side chain conformations, or rotamers, and a forcefield to guide the structure to low-energy conformations. Recently, deep learning (DL) based methods (such as DLPacker, AttnPacker, and DiffPack) have demonstrated state-of-the-art predictions and speed in the PSCP task. Building off the success of geometric graph neural networks for protein modeling, we present the Protein Invariant Point Packer (PIPPack) which effectively processes local structural and sequence information to produce realistic, idealized side chain coordinates using <math><mrow><mi>χ</mi></mrow> </math> -angle distribution predictions and geometry-aware invariant point message passing (IPMP). On a test set of ∼1400 high-quality protein chains, PIPPack is highly competitive with other state-of-the-art PSCP methods in rotamer recovery and per-residue RMSD but is significantly faster.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094500","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

Application of artificial intelligence and machine learning techniques to the analysis of dynamic protein sequences. 将人工智能和机器学习技术应用于动态蛋白质序列分析。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-10-01 Epub Date: 2024-05-29 DOI: 10.1002/prot.26704

David C Kombo, Matthew J LaMarche, Chilaluck C Konkankit, S Rackovsky

{"title":"Application of artificial intelligence and machine learning techniques to the analysis of dynamic protein sequences.","authors":"David C Kombo, Matthew J LaMarche, Chilaluck C Konkankit, S Rackovsky","doi":"10.1002/prot.26704","DOIUrl":"10.1002/prot.26704","url":null,"abstract":"We apply methods of Artificial Intelligence and Machine Learning to protein dynamic bioinformatics. We rewrite the sequences of a large protein data set, containing both folded and intrinsically disordered molecules, using a representation developed previously, which encodes the intrinsic dynamic properties of the naturally occurring amino acids. We Fourier analyze the resulting sequences. It is demonstrated that classification models built using several different supervised learning methods are able to successfully distinguish folded from intrinsically disordered proteins from sequence alone. It is further shown that the most important sequence property for this discrimination is the sequence mobility, which is the sequence averaged value of the residue-specific average alpha carbon B factor. This is in agreement with previous work, in which we have demonstrated the central role played by the sequence mobility in protein dynamic bioinformatics and biophysics. This finding opens a path to the application of dynamic bioinformatics, in combination with machine learning algorithms, to a range of significant biomedical problems.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11511649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141162698","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

Computational analysis of propeptide-containing proteins and prediction of their post-cleavage conformation changes. 含肽蛋白质的计算分析及其裂解后构象变化的预测。

IF 3.2 4区生物学

Proteins-Structure Function and Bioinformatics Pub Date : 2024-10-01 Epub Date: 2024-05-22 DOI: 10.1002/prot.26702

Jimin Pei, Lisa N Kinch, Qian Cong

{"title":"Computational analysis of propeptide-containing proteins and prediction of their post-cleavage conformation changes.","authors":"Jimin Pei, Lisa N Kinch, Qian Cong","doi":"10.1002/prot.26702","DOIUrl":"10.1002/prot.26702","url":null,"abstract":"A propeptide is removed from a precursor protein to generate its active or mature form. Propeptides play essential roles in protein folding, transportation, and activation and are present in about 2.3% of reviewed proteins in the UniProt database. They are often found in secreted or membrane-bound proteins including proteolytic enzymes, hormones, and toxins. We identified a variety of globular and nonglobular Pfam domains in protein sequences designated as propeptides, some of which form intramolecular interactions with other domains in the mature proteins. Propeptide-containing enzymes mostly function as proteases, as they are depleted in other enzyme classes such as hydrolases acting on DNA and RNA, isomerases, and lyases. We applied AlphaFold to generate structural models for over 7000 proteins with propeptides having no less than 20 residues. Analysis of residue contacts in these models revealed conformational changes for over 300 proteins before and after the cleavage of the propeptide. Examples of conformation change occur in several classes of proteolytic enzymes in the families of subtilisins, trypsins, aspartyl proteases, and thermolysin-like metalloproteases. In most of the observed cases, cleavage of the propeptide releases the constraints imposed by the covalent bond between the propeptide and the mature protein, and cleavage enables stronger interactions between the propeptide and the mature protein. These findings suggest that post-cleavage propeptides could play critical roles in regulating the activity of mature proteins.","PeriodicalId":56271,"journal":{"name":"Proteins-Structure Function and Bioinformatics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141077309","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