Proteins: Structure最新文献_第10页

Structural complementarity of distance constraints obtained from chemical cross‐linking and amino acid coevolution 从化学交联和氨基酸共同进化中获得的距离约束的结构互补性

Proteins: Structure Pub Date : 2020-04-01 DOI: 10.1002/prot.25843

Ricardo N Dos Santos, G. F. Bottino, F. Gozzo, F. Morcos, L. Martínez

引用次数: 3

RMSD analysis of structures of the bacterial protein FimH identifies five conformations of its lectin domain 细菌蛋白FimH结构的RMSD分析鉴定了其凝集素结构域的五种构象

Proteins: Structure Pub Date : 2020-04-01 DOI: 10.1002/prot.25840

Pearl Magala, R. Klevit, W. Thomas, E. Sokurenko, R. Stenkamp

{"title":"RMSD analysis of structures of the bacterial protein FimH identifies five conformations of its lectin domain","authors":"Pearl Magala, R. Klevit, W. Thomas, E. Sokurenko, R. Stenkamp","doi":"10.1002/prot.25840","DOIUrl":"https://doi.org/10.1002/prot.25840","url":null,"abstract":"FimH is a bacterial adhesin protein located at the tip of Escherichia coli fimbria that functions to adhere bacteria to host cells. Thus, FimH is a critical factor in bacterial infections such as urinary tract infections and is of interest in drug development. It is also involved in vaccine development and as a model for understanding shear‐enhanced catch bond cell adhesion. To date, over 60 structures have been deposited in the Protein Data Bank showing interactions between FimH and mannose ligands, potential inhibitors, and other fimbrial proteins. In addition to providing insights about ligand recognition and fimbrial assembly, these structures provide insights into conformational changes in the two domains of FimH that are critical for its function. To gain further insights into these structural changes, we have superposed FimH's mannose binding lectin domain in all these structures and categorized the structures into five groups of lectin domain conformers using RMSD as a metric. Many structures also include the pilin domain, which anchors FimH to the fimbriae and regulates the conformation and function of the lectin domain. For these structures, we have also compared the relative orientations of the two domains. These structural analyses enhance our understanding of the conformational changes associated with FimH ligand binding and domain‐domain interactions, including its catch bond behavior through allosteric action of force in bacterial adhesion.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"62 1","pages":"593 - 603"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86720898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Proton relay network in P450cam formed upon docking of putidaredoxin 质子中继网络在p450凸轮对接后形成

Proteins: Structure Pub Date : 2020-04-01 DOI: 10.1002/prot.25835

I. Ugur, P. Chandrasekhar

{"title":"Proton relay network in P450cam formed upon docking of putidaredoxin","authors":"I. Ugur, P. Chandrasekhar","doi":"10.1002/prot.25835","DOIUrl":"https://doi.org/10.1002/prot.25835","url":null,"abstract":"Cytochromes P450 are versatile heme‐based enzymes responsible for vital life processes. Of these, P450cam (substrate camphor) has been most studied. Despite this, precise mechanisms of the key O─O cleavage step remain partly elusive to date; effects observed in various enzyme mutants remain partly unexplained. We have carried out extended (to 1000 ns) MM‐MD and follow‐on quantum mechanics/molecular mechanics computations, both on the well‐studied FeOO state and on Cpd(0) (compound 0). Our simulations include (all camphor‐bound): (a) WT (wild type), FeOO state. (b) WT, Cpd(0). (c) Pdx (Putidaredoxin, redox partner of P450)‐docked‐WT, FeOO state. (d) Pdx‐docked WT, Cpd(0). (e) Pdx‐docked T252A mutant, Cpd(0). Among our key findings: (a) Effect of Pdx docking appears to go far beyond that indicated in prior studies: it leads to specific alterations in secondary structure that create the crucial proton relay network. (b) Specific proton relay networks we identify are: FeOO(H)⋯T252⋯nH 2O⋯D251 in WT; FeOO(H)⋯nH 2O⋯D251 in T252A mutant; both occur with Pdx docking. (c) Direct interaction of D251 with –FeOOH is, respectively, rare/frequent in WT/T252A mutant. (d) In WT, T252 is in the proton relay network. (e) Positioning of camphor appears significant: when camphor is part of H‐bonding network, second protonation appears to be facilitated.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"27 1","pages":"558 - 572"},"PeriodicalIF":0.0,"publicationDate":"2020-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91163922","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

All‐atom molecular dynamics simulations reveal how kinesin transits from one‐head‐bound to two‐heads‐bound state 全原子分子动力学模拟揭示了动力学蛋白如何从一个头结合状态过渡到两个头结合状态

Proteins: Structure Pub Date : 2020-04-01 DOI: 10.1002/prot.25833

Xiao-Xuan Shi, Si-Kao Guo, Pengye Wang, Hong Chen, P. Xie

引用次数: 16

Issue Information ‐ Forthcoming 发行信息‐即将发布

Proteins: Structure Pub Date : 2020-03-03 DOI: 10.1002/prot.25719

引用次数: 0

Issue Information ‐ Table of Content 发行信息‐内容表

Proteins: Structure Pub Date : 2020-03-03 DOI: 10.1002/prot.25717

引用次数: 0

Protonation state of the selectivity filter of bacterial voltage‐gated sodium channels is modulated by ions 细菌电压门控钠通道的选择性过滤器的质子化状态是由离子调节的

Proteins: Structure Pub Date : 2020-03-01 DOI: 10.1002/prot.25831

A. Damjanovic, Ada Y. Chen, R. Rosenberg, D. Roe, Xiongwu Wu, B. Brooks

{"title":"Protonation state of the selectivity filter of bacterial voltage‐gated sodium channels is modulated by ions","authors":"A. Damjanovic, Ada Y. Chen, R. Rosenberg, D. Roe, Xiongwu Wu, B. Brooks","doi":"10.1002/prot.25831","DOIUrl":"https://doi.org/10.1002/prot.25831","url":null,"abstract":"The selectivity filter (SF) of bacterial voltage‐gated sodium channels consists of four glutamate residues arranged in a C4 symmetry. The protonation state population of this tetrad is unclear. To address this question, we simulate the pore domain of bacterial voltage‐gated sodium channel of Magnetococcus sp. (NavMs) through constant pH methodology in explicit solvent and free energy perturbation calculations. We find that at physiological pH the fully deprotonated as well as singly and doubly protonated states of the SF appear feasible, and that the calculated pKa decreases with each additional bound ion, suggesting that a decrease in the number of ions in the pore can lead to protonation of the SF. Previous molecular dynamics simulations have suggested that protonation can lead to a decrease in the conductance, but no pKa calculations were performed. We confirm a decreased ionic population of the pore with protonation, and also observe structural symmetry breaking triggered by protonation; the SF of the deprotonated channel is closest to the C4 symmetry observed in crystal structures of the open state, while the SF of protonated states display greater levels of asymmetry which could lead to transition to the inactivated state which possesses a C2 symmetry in the crystal structure. We speculate that the decrease in the number of ions near the mouth of the channel, due to either random fluctuations or ion depletion due to conduction, could be a self‐regulatory mechanism resulting in a nonconducting state that functionally resembles inactivated states.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"73 1","pages":"527 - 539"},"PeriodicalIF":0.0,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86005289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7

Delineation of a new structural motif involving NHN γ‐turn 描述一个涉及NHN γ - turn的新结构基序

Proteins: Structure Pub Date : 2020-03-01 DOI: 10.1002/prot.25820

Jesmita Dhar, R. Kishore, P. Chakrabarti

{"title":"Delineation of a new structural motif involving NHN γ‐turn","authors":"Jesmita Dhar, R. Kishore, P. Chakrabarti","doi":"10.1002/prot.25820","DOIUrl":"https://doi.org/10.1002/prot.25820","url":null,"abstract":"Macromolecules are characterized by distinctive arrangement of hydrogen bonds. Different patterns of hydrogen bonds give rise to distinct and stable structural motifs. An analysis of 4114 non‐redundant protein chains reveals the existence of a three‐residue, (i − 1) to (i + 1), structural motif, having two hydrogen‐bonded five‐membered pseudo rings (the first, an NH···OC involving the first residue, and the second being NH∙∙∙N involving the last two residues), separated by a peptide bond. There could be an additional hydrogen bond between the side‐chain at (i‐1) and the main‐chain NH of (i + 1). The average backbone torsion angles of −76(±21)° and – 12(±17)° at i creates a tight turn in the polypeptide chain, akin to a γ‐turn. Indeed, a search of three‐residue fragments with restriction on the terminal Cα···Cα distance and the existence of the two pseudo rings on either side revealed the presence 14 846 cases of a variant, termed NHN γ‐turn, distinct from the NHO γ‐turn (2032 cases) that has traditionally been characterized by the presence of NHO hydrogen bond linking the terminal main‐chain atoms. As in the latter, the newly identified γ‐turns are also of two types—classical and inverse, occurring in the ratio of 1:6. The propensities of residues to occur in these turns and their secondary structural features have been enumerated. An understanding of these turns would be useful for structure prediction and loop modeling, and may serve as models to represent some of the unfolded state or disordered region in proteins.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"87 1","pages":"431 - 439"},"PeriodicalIF":0.0,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73453239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Accessory mutations balance the marginal stability of the HIV‐1 protease in drug resistance 辅助突变平衡了耐药过程中HIV‐1蛋白酶的边缘稳定性

Proteins: Structure Pub Date : 2020-03-01 DOI: 10.1002/prot.25826

T. Weikl, B. Hemmateenejad

{"title":"Accessory mutations balance the marginal stability of the HIV‐1 protease in drug resistance","authors":"T. Weikl, B. Hemmateenejad","doi":"10.1002/prot.25826","DOIUrl":"https://doi.org/10.1002/prot.25826","url":null,"abstract":"The HIV‐1 protease is a major target of inhibitor drugs in AIDS therapies. The therapies are impaired by mutations of the HIV‐1 protease that can lead to resistance to protease inhibitors. These mutations are classified into major mutations, which usually occur first and clearly reduce the susceptibility to protease inhibitors, and minor, accessory mutations that occur later and individually do not substantially affect the susceptibility to inhibitors. Major mutations are predominantly located in the active site of the HIV‐1 protease and can directly interfere with inhibitor binding. Minor mutations, in contrast, are typically located distal to the active site. A central question is how these distal mutations contribute to resistance development. In this article, we present a systematic computational investigation of stability changes caused by major and minor mutations of the HIV‐1 protease. As most small single‐domain proteins, the HIV‐1 protease is only marginally stable. Mutations that destabilize the folded, active state of the protease therefore can shift the conformational equilibrium towards the unfolded, inactive state. We find that the most frequent major mutations destabilize the HIV‐1 protease, whereas roughly half of the frequent minor mutations are stabilizing. An analysis of protease sequences from patients in treatment indicates that the stabilizing minor mutations are frequently correlated with destabilizing major mutations, and that highly resistant HIV‐1 proteases exhibit significant fractions of stabilizing mutations. Our results thus indicate a central role of minor mutations in balancing the marginal stability of the protease against the destabilization induced by the most frequent major mutations.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"88 1","pages":"476 - 484"},"PeriodicalIF":0.0,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81448081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 6

Molecular basis of drug resistance in smoothened receptor: An in silico study of protein resistivity and specificity 平滑受体耐药的分子基础:蛋白质电阻率和特异性的计算机研究

Proteins: Structure Pub Date : 2020-03-01 DOI: 10.1002/prot.25830

N. Sinha, S. Chowdhury, R. Sarkar

{"title":"Molecular basis of drug resistance in smoothened receptor: An in silico study of protein resistivity and specificity","authors":"N. Sinha, S. Chowdhury, R. Sarkar","doi":"10.1002/prot.25830","DOIUrl":"https://doi.org/10.1002/prot.25830","url":null,"abstract":"Smoothened (SMO) antagonist Vismodegib effectively inhibits the Hedgehog pathway in proliferating cancer cells. In early stage of treatment, Vismodegib exhibited promising outcomes to regress the tumors cells, but ultimately relapsed due to the drug resistive mutations in SMO mostly occurring before (primary mutations G497W) or after (acquired mutations D473H/Y) anti‐SMO therapy. This study investigates the unprecedented insights of structural and functional mechanism hindering the binding of Vismodegib with sensitive and resistant mutant variants of SMO (SMOMut). Along with the basic dynamic understanding of Vismodegib‐SMO complexes, network propagation theory based on heat diffusion principles is first time applied here to identify the modules of residues influenced by the individual mutations. The allosteric modulation by GLY497 residue in Vismodegib bound SMO wild‐type (SMOWT) conformation depicts the interconnections of intermediate residues of SMO with the atom of Vismodegib and identify two important motifs (E‐X‐P‐L) and (Q‐A‐N‐V‐T‐I‐G) mediating this allosteric regulation. In this study a novel computational framework based on the heat diffusion principle is also developed, which identify significant residues of allosteric site causing drug resistivity in SMOMut. This framework could also be useful for assessing the potential allosteric sites of different other proteins. Moreover, previously reported novel inhibitor “ZINC12368305,” which is proven to make an energetically favorable complex with SMOWT is chosen as a control sample to assess the impact of receptor mutation on its binding and subsequently identify the important factors that govern binding disparity between Vismodegib and ZINC12368305 bound SMOWT/Mut conformations.","PeriodicalId":20789,"journal":{"name":"Proteins: Structure","volume":"69 1","pages":"514 - 526"},"PeriodicalIF":0.0,"publicationDate":"2020-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90593651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 7