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Discovery and characterization of a pan-betacoronavirus S2-binding antibody 发现泛胸腺病毒 S2 结合抗体并确定其特性
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-25 DOI: 10.1016/j.str.2024.08.022
Nicole V. Johnson, Steven C. Wall, Kevin J. Kramer, Clinton M. Holt, Sivakumar Periasamy, Simone I. Richardson, Nelia P. Manamela, Naveenchandra Suryadevara, Emanuele Andreano, Ida Paciello, Giulio Pierleoni, Giulia Piccini, Ying Huang, Pan Ge, James D. Allen, Naoko Uno, Andrea R. Shiakolas, Kelsey A. Pilewski, Rachel S. Nargi, Rachel E. Sutton, Ivelin S. Georgiev
The continued emergence of deadly human coronaviruses from animal reservoirs highlights the need for pan-coronavirus interventions for effective pandemic preparedness. Here, using linking B cell receptor to antigen specificity through sequencing (LIBRA-seq), we report a panel of 50 coronavirus antibodies isolated from human B cells. Of these, 54043-5 was shown to bind the S2 subunit of spike proteins from alpha-, beta-, and deltacoronaviruses. A cryoelectron microscopy (cryo-EM) structure of 54043-5 bound to the prefusion S2 subunit of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike defined an epitope at the apex of S2 that is highly conserved among betacoronaviruses. Although non-neutralizing, 54043-5 induced Fc-dependent antiviral responses in vitro, including antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). In murine SARS-CoV-2 challenge studies, protection against disease was observed after introduction of Leu234Ala, Leu235Ala, and Pro329Gly (LALA-PG) substitutions in the Fc region of 54043-5. Together, these data provide new insights into the protective mechanisms of non-neutralizing antibodies and define a broadly conserved epitope within the S2 subunit.
致命的人类冠状病毒不断从动物病毒库中出现,这凸显了为有效防范大流行而采取泛冠状病毒干预措施的必要性。在这里,我们通过测序(LIBRA-seq)将 B 细胞受体与抗原特异性联系起来,报告了从人类 B 细胞中分离出的 50 种冠状病毒抗体。其中,54043-5 被证明能与α-、β- 和 deltacoronaviruses 的尖峰蛋白 S2 亚基结合。54043-5 与严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)尖峰的预融合 S2 亚基结合的冷冻电镜(cryo-EM)结构确定了 S2 顶点的表位,该表位在 betacoronaviruses 中高度保守。虽然 54043-5 不具有中和作用,但它能在体外诱导 Fc 依赖性抗病毒反应,包括抗体依赖性细胞毒性(ADCC)和抗体依赖性细胞吞噬作用(ADCP)。在小鼠 SARS-CoV-2 挑战研究中,在 54043-5 的 Fc 区引入 Leu234Ala、Leu235Ala 和 Pro329Gly(LALA-PG)替代后,可观察到对疾病的保护作用。总之,这些数据为非中和抗体的保护机制提供了新的见解,并确定了 S2 亚基中一个广泛保守的表位。
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引用次数: 0
Improved higher resolution cryo-EM structures reveal the binding modes of hERG channel inhibitors 更高分辨率的低温电子显微镜结构揭示了 hERG 通道抑制剂的结合模式
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-24 DOI: 10.1016/j.str.2024.08.021
Yasuomi Miyashita, Toshio Moriya, Takafumi Kato, Masato Kawasaki, Satoshi Yasuda, Naruhiko Adachi, Kano Suzuki, Satoshi Ogasawara, Tetsuichiro Saito, Toshiya Senda, Takeshi Murata
During drug discovery, it is crucial to exclude compounds with toxic effects. The human ether-à-go-go-related gene (hERG) channel is essential for maintaining cardiac repolarization and is a critical target in drug safety evaluation due to its role in drug-induced arrhythmias. Inhibition of the hERG channel can lead to severe cardiac issues, including Torsades de Pointes tachycardia. Understanding hERG inhibition mechanisms is essential to avoid these toxicities. Several structural studies have elucidated the interactions between inhibitors and hERG. However, orientation and resolution issues have so far limited detailed insights. Here, we used digitonin to analyze the apo state of hERG, which resolved orientation issues and improved the resolution. We determined the structure of hERG bound to astemizole, showing a clear map in the pore pathway. Using this strategy, we also analyzed the binding modes of E-4031 and pimozide. These insights into inhibitor interactions with hERG may aid safer drug design and enhance cardiac safety.
在药物发现过程中,排除具有毒性作用的化合物至关重要。人ether-à-go-go相关基因(hERG)通道对维持心脏复极至关重要,由于它在药物诱发的心律失常中的作用,因此是药物安全性评估的关键靶点。抑制 hERG 通道可导致严重的心脏问题,包括 Torsades de Pointes 心动过速。了解 hERG 抑制机制对于避免这些毒性至关重要。一些结构研究已经阐明了抑制剂与 hERG 之间的相互作用。然而,定向和分辨率问题迄今限制了详细的深入研究。在这里,我们使用地高辛来分析 hERG 的 apo 状态,从而解决了取向问题并提高了分辨率。我们确定了与阿司咪唑结合的 hERG 的结构,显示了孔途径的清晰图谱。利用这一策略,我们还分析了 E-4031 和匹莫齐特的结合模式。这些关于抑制剂与 hERG 相互作用的见解可能有助于更安全的药物设计并提高心脏安全性。
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引用次数: 0
Advances in the field of RNA 3D structure prediction and modeling, with purely theoretical approaches, and with the use of experimental data 利用纯理论方法和实验数据在 RNA 3D 结构预测和建模领域取得的进展
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-24 DOI: 10.1016/j.str.2024.08.015
Sunandan Mukherjee, S. Naeim Moafinejad, Nagendar Goud Badepally, Katarzyna Merdas, Janusz M. Bujnicki
Recent advancements in RNA three-dimensional (3D) structure prediction have provided significant insights into RNA biology, highlighting the essential role of RNA in cellular functions and its therapeutic potential. This review summarizes the latest developments in computational methods, particularly the incorporation of artificial intelligence and machine learning, which have improved the efficiency and accuracy of RNA structure predictions. We also discuss the integration of new experimental data types, including cryoelectron microscopy (cryo-EM) techniques and high-throughput sequencing, which have transformed RNA structure modeling. The combination of experimental advances with computational methods represents a significant leap in RNA structure determination. We review the outcomes of RNA-Puzzles and critical assessment of structure prediction (CASP) challenges, which assess the state of the field and limitations of existing methods. Future perspectives are discussed, focusing on the impact of RNA 3D structure prediction on understanding RNA mechanisms and its implications for drug discovery and RNA-targeted therapies, opening new avenues in molecular biology.
最近在 RNA 三维(3D)结构预测方面取得的进展为 RNA 生物学提供了重要见解,凸显了 RNA 在细胞功能中的重要作用及其治疗潜力。本综述总结了计算方法的最新发展,特别是人工智能和机器学习的应用,它们提高了 RNA 结构预测的效率和准确性。我们还讨论了新实验数据类型的整合,包括低温电子显微镜(cryo-EM)技术和高通量测序技术,它们改变了 RNA 结构建模。实验进展与计算方法的结合代表了 RNA 结构测定领域的重大飞跃。我们回顾了 RNA-Puzzles 和结构预测关键评估(CASP)挑战的成果,评估了该领域的现状和现有方法的局限性。我们还讨论了未来的前景,重点是 RNA 三维结构预测对理解 RNA 机制的影响及其对药物发现和 RNA 靶向疗法的影响,为分子生物学开辟了新的途径。
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引用次数: 0
An AI-informed NMR structure reveals an extraordinary LETM1 F-EF-hand domain that functions as a two-way regulator of mitochondrial calcium 人工智能信息核磁共振结构揭示了一个非同寻常的 LETM1 F-EF 手结构域,它是线粒体钙的双向调节器
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-23 DOI: 10.1016/j.str.2024.08.020
Qi-Tong Lin, Danielle M. Colussi, Taylor Lake, Peter B. Stathopulos
AlphaFold can accurately predict static protein structures but does not account for solvent conditions. Human leucine zipper EF-hand transmembrane protein-1 (LETM1) has one sequence-identifiable EF-hand but how calcium (Ca2+) affects structure and function remains enigmatic. Here, we used highly confident AlphaFold Cα predictions to guide nuclear Overhauser effect (NOE) assignments and structure calculation of the LETM1 EF-hand in the presence of Ca2+. The resultant NMR structure exposes pairing between a partial loop-helix and full helix-loop-helix, forming an unprecedented F-EF-hand with non-canonical Ca2+ coordination but enhanced hydrophobicity for protein interactions compared to calmodulin. The structure also reveals the basis for pH sensing at the link between canonical and partial EF-hands. Functionally, mutations that augmented or weakened Ca2+ binding increased or decreased matrix Ca2+, respectively, establishing F-EF as a two-way mitochondrial Ca2+ regulator. Thus, we show how to synergize AI prediction with NMR data, elucidating a solution-specific and extraordinary LETM1 F-EF-hand.
AlphaFold 可以准确预测静态蛋白质结构,但不能考虑溶剂条件。人类亮氨酸拉链EF-手跨膜蛋白-1(LETM1)有一个序列可识别的EF-手,但钙(Ca2+)如何影响结构和功能仍然是个谜。在这里,我们使用高度可靠的 AlphaFold Cα 预测来指导核奥弗霍塞尔效应(NOE)分配和 Ca2+ 存在时 LETM1 EF-手的结构计算。由此产生的核磁共振结构揭示了部分环-螺旋和全螺旋-环-螺旋之间的配对,形成了一种前所未有的 F-EF 手,与钙调素相比,它具有非典型 Ca2+ 配位,但蛋白质相互作用的疏水性增强。该结构还揭示了典型 EF 手和部分 EF 手之间的 pH 感知基础。在功能上,增强或减弱 Ca2+ 结合的突变分别增加或减少了基质 Ca2+,从而确立了 F-EF 作为线粒体 Ca2+ 双向调节因子的地位。因此,我们展示了如何将人工智能预测与核磁共振数据协同作用,阐明了溶液特异性和非凡的 LETM1 F-EF 手。
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引用次数: 0
Molecular basis of proteolytic cleavage regulation by the extracellular matrix receptor dystroglycan 细胞外基质受体肌冻蛋白调节蛋白水解裂解的分子基础
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-20 DOI: 10.1016/j.str.2024.08.019
Michael J.M. Anderson, Amanda N. Hayward, Adam T. Smiley, Ke Shi, Matthew R. Pawlak, Eric J. Aird, Eva Grant, Lauren Greenberg, Hideki Aihara, Robert L. Evans, Christopher Ulens, Wendy R. Gordon

The dystrophin-glycoprotein-complex (DGC), anchored by the transmembrane protein dystroglycan, functions to mechanically link the extracellular matrix and actin cytoskeleton. Breaking this connection is associated with diseases such as muscular dystrophy, yet cleavage of dystroglycan by matrix-metalloproteinases (MMPs) remains an understudied mechanism to disrupt the DGC. We determined the crystal structure of the membrane-adjacent domain (amino acids 491–722) of E. coli expressed human dystroglycan to understand MMP cleavage regulation. The structural model includes tandem immunoglobulin-like (IGL) and sperm/enterokinase/agrin-like (SEAL) domains, which support proteolysis in diverse receptors to facilitate mechanotransduction, membrane protection, and viral entry. The structure reveals a C-terminal extension that buries the MMP site by packing into a hydrophobic pocket, a unique mechanism of MMP cleavage regulation. We further demonstrate structure-guided and disease-associated mutations disrupt proteolytic regulation using a cell-surface proteolysis assay. Thus disrupted proteolysis is a potentially relevant mechanism for “breaking” the DGC link to contribute to disease pathogenesis.

肌营养蛋白-糖蛋白复合物(DGC)由跨膜蛋白肌营养蛋白锚定,具有机械连接细胞外基质和肌动蛋白细胞骨架的功能。破坏这种连接与肌肉萎缩症等疾病有关,但基质金属蛋白酶(MMPs)对淀粉样糖的裂解仍是破坏 DGC 的一种未被充分研究的机制。我们测定了大肠杆菌表达的人类肌营养不良症蛋白的膜邻接结构域(491-722 氨基酸)的晶体结构,以了解 MMP 的裂解调控。该结构模型包括串联免疫球蛋白样(IGL)结构域和精子/肠激酶/异体蛋白样(SEAL)结构域,它们支持不同受体的蛋白水解,以促进机械传导、膜保护和病毒进入。该结构揭示了一个 C 端延伸,它通过填入一个疏水袋来掩埋 MMP 位点,这是一种独特的 MMP 裂解调节机制。我们还利用细胞表面蛋白水解试验进一步证明了结构引导和疾病相关突变会破坏蛋白水解调节。因此,蛋白水解紊乱是 "打破 "DGC 链接并导致疾病发病的潜在相关机制。
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引用次数: 0
The human touch: Utilizing AlphaFold 3 to analyze structures of endogenous metabolons 人情味利用 AlphaFold 3 分析内源性代谢物的结构
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-19 DOI: 10.1016/j.str.2024.08.018
Toni K. Träger, Christian Tüting, Panagiotis L. Kastritis

Computational structural biology aims to accurately predict biomolecular complexes with AlphaFold 3 spearheading the field. However, challenges loom for structural analysis, especially when complex assemblies such as the pyruvate dehydrogenase complex (PDHc), which catalyzes the link reaction in cellular respiration, are studied. PDHc subcomplexes are challenging to predict, particularly interactions involving weaker, lower-affinity subcomplexes. Supervised modeling, i.e., integrative structural biology, will continue to play a role in fine-tuning this type of prediction (e.g., removing clashes, rebuilding loops/disordered regions, and redocking interfaces). 3D analysis of endogenous metabolic complexes continues to require, in addition to AI, precise and multi-faceted interrogation methods.

计算结构生物学旨在准确预测生物分子复合物,AlphaFold 3 是这一领域的先锋。然而,结构分析面临着挑战,尤其是在研究丙酮酸脱氢酶复合物(PDHc)等复杂复合物时,该复合物催化了细胞呼吸中的链接反应。PDHc 亚复合物的预测具有挑战性,尤其是涉及较弱、亲和力较低的亚复合物的相互作用。有监督的建模,即综合结构生物学,将继续在微调这类预测方面发挥作用(例如,消除冲突、重建环路/紊乱区域以及重新对接界面)。除了人工智能,内源代谢复合物的三维分析仍然需要精确和多方面的分析方法。
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引用次数: 0
AlphaFold with conformational sampling reveals the structural landscape of homorepeats 带有构象取样功能的 AlphaFold 揭示了同源重复序列的结构景观
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1016/j.str.2024.08.016
David Fernandez Bonet, Shahrayar Ranyai, Luay Aswad, David P. Lane, Marie Arsenian-Henriksson, Michael Landreh, Dilraj Lama

Homorepeats are motifs with reiterations of the same amino acid. They are prevalent in proteins associated with diverse physiological functions but also linked to several pathologies. Structural characterization of homorepeats has remained largely elusive, primarily because they generally occur in the disordered regions or proteins. Here, we address this subject by combining structures derived from machine learning with conformational sampling through physics-based simulations. We find that hydrophobic homorepeats have a tendency to fold into structured secondary conformations, while hydrophilic ones predominantly exist in unstructured states. Our data show that the flexibility rendered by disorder is a critical component besides the chemical feature that drives homorepeats composition toward hydrophilicity. The formation of regular secondary structures also influences their solubility, as pathologically relevant homorepeats display a direct correlation between repeat expansion, induction of helicity, and self-assembly. Our study provides critical insights into the conformational landscape of protein homorepeats and their structure-activity relationship.

同源重复是指相同氨基酸的重复。它们普遍存在于与多种生理功能相关的蛋白质中,但也与多种病症有关。同源重复序列的结构特征在很大程度上仍然难以确定,这主要是因为它们通常出现在蛋白质的无序区域。在这里,我们通过基于物理的模拟,将机器学习得出的结构与构象取样相结合,解决了这一问题。我们发现,疏水性同源蛋白倾向于折叠成结构化的次级构象,而亲水性同源蛋白则主要存在于非结构化状态。我们的数据表明,除了化学特征之外,无序所带来的灵活性也是促使同源中继物组成趋向亲水性的关键因素。规则二级结构的形成也会影响它们的溶解度,因为与病理相关的同源中继物在重复扩展、螺旋诱导和自组装之间显示出直接的相关性。我们的研究为了解蛋白质同源中继蛋白的构象格局及其结构-活性关系提供了重要见解。
{"title":"AlphaFold with conformational sampling reveals the structural landscape of homorepeats","authors":"David Fernandez Bonet, Shahrayar Ranyai, Luay Aswad, David P. Lane, Marie Arsenian-Henriksson, Michael Landreh, Dilraj Lama","doi":"10.1016/j.str.2024.08.016","DOIUrl":"https://doi.org/10.1016/j.str.2024.08.016","url":null,"abstract":"<p>Homorepeats are motifs with reiterations of the same amino acid. They are prevalent in proteins associated with diverse physiological functions but also linked to several pathologies. Structural characterization of homorepeats has remained largely elusive, primarily because they generally occur in the disordered regions or proteins. Here, we address this subject by combining structures derived from machine learning with conformational sampling through physics-based simulations. We find that hydrophobic homorepeats have a tendency to fold into structured secondary conformations, while hydrophilic ones predominantly exist in unstructured states. Our data show that the flexibility rendered by disorder is a critical component besides the chemical feature that drives homorepeats composition toward hydrophilicity. The formation of regular secondary structures also influences their solubility, as pathologically relevant homorepeats display a direct correlation between repeat expansion, induction of helicity, and self-assembly. Our study provides critical insights into the conformational landscape of protein homorepeats and their structure-activity relationship.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":"186 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142237024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Lys716 in the transmembrane domain of yeast mitofusin Fzo1 modulates anchoring and fusion 酵母丝裂蛋白Fzo1跨膜结构域中的Lys716调节锚定和融合
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-18 DOI: 10.1016/j.str.2024.08.017
Raphaëlle Versini, Marc Baaden, Laetitia Cavellini, Mickaël M. Cohen, Antoine Taly, Patrick F.J. Fuchs

Outer mitochondrial membrane fusion, a vital cellular process, is mediated by mitofusins. However, the underlying molecular mechanism remains elusive. We have performed extensive multiscale molecular dynamics simulations to predict a model of the transmembrane (TM) domain of the yeast mitofusin Fzo1. Coarse-grained simulations of the two TM domain helices, TM1 and TM2, reveal a stable interface, which is controlled by the charge status of residue Lys716. Atomistic replica-exchange simulations further tune our model, which is confirmed by a remarkable agreement with an independent AlphaFold2 (AF2) prediction of Fzo1 in complex with its fusion partner Ugo1. Furthermore, the presence of the TM domain destabilizes the membrane, even more if Lys716 is charged, which can be an asset for initiating fusion. The functional role of Lys716 was confirmed with yeast experiments, which show that mutating Lys716 to a hydrophobic residue prevents mitochondrial fusion.

线粒体外膜融合是一个重要的细胞过程,它由丝裂蛋白介导。然而,其潜在的分子机制仍然难以捉摸。我们进行了大量的多尺度分子动力学模拟,以预测酵母丝裂蛋白 Fzo1 的跨膜(TM)结构域模型。对两个 TM 结构域螺旋(TM1 和 TM2)的粗粒度模拟揭示了一个稳定的界面,该界面由残基 Lys716 的电荷状态控制。原子论复制交换模拟进一步调整了我们的模型,这一点通过 Fzo1 与其融合伙伴 Ugo1 复合物的独立 AlphaFold2(AF2)预测结果的显著一致性得到了证实。此外,TM 结构域的存在破坏了膜的稳定性,如果 Lys716 带有电荷,则破坏程度更大,而这正是启动融合的有利条件。酵母实验证实了 Lys716 的功能作用,实验表明,将 Lys716 突变为疏水残基会阻止线粒体融合。
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引用次数: 0
The future of integrated structural biology 综合结构生物学的未来
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-17 DOI: 10.1016/j.str.2024.08.014
Harald Schwalbe, Pauline Audergon, Natalie Haley, Claudia Alen Amaro, Jon Agirre, Marc Baldus, Lucia Banci, Wolfgang Baumeister, Martin Blackledge, Jose Maria Carazo, Kristina Djinovic Carugo, Patrick Celie, Isabella Felli, Darren J. Hart, Thomas Hauß, Lari Lehtiö, Kresten Lindorff-Larsen, José Márquez, André Matagne, Roberta Pierattelli, Matthias Wilmanns

Instruct-ERIC, “the European Research Infrastructure Consortium for Structural biology research,” is a pan-European distributed research infrastructure making high-end technologies and methods in structural biology available to users. Here, we describe the current state-of-the-art of integrated structural biology and discuss potential future scientific developments as an impulse for the scientific community, many of which are located in Europe and are associated with Instruct. We reflect on where to focus scientific and technological initiatives within the distributed Instruct research infrastructure. This review does not intend to make recommendations on funding requirements or initiatives directly, neither at the national nor the European level. However, it addresses future challenges and opportunities for the field, and foresees the need for a stronger coordination within the European and international research field of integrated structural biology to be able to respond timely to thematic topics that are often prioritized by calls for funding addressing societal needs.

欧洲结构生物学研究基础设施联盟"(Instruct-ERIC)是一个泛欧分布式研究基础设施,为用户提供结构生物学方面的高端技术和方法。在此,我们介绍了当前综合结构生物学的最新发展,并讨论了未来潜在的科学发展,以此推动科学界的发展,其中许多科学界都位于欧洲,并与 Instruct 有关。我们思考了在分布式 Instruct 研究基础设施内应将科学和技术倡议的重点放在哪里。无论是在国家层面还是在欧洲层面,本次审查都无意直接就资金需求或倡议提出建议。不过,它探讨了该领域未来的挑战和机遇,并预见到在欧洲和国际综合结构生物学研究领域内加强协调的必要性,以便能够及时应对往往被针对社会需求的筹资呼吁列为优先事项的专题。
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引用次数: 0
Structural characterization of the POTRA domains from A. baumannii reveals new conformations in BamA 鲍曼不动杆菌 POTRA 结构域的结构表征揭示了 BamA 的新构象
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-17 DOI: 10.1016/j.str.2024.08.013
Claire Overly Cottom, Robert Stephenson, Dante Ricci, Lixinhao Yang, James C. Gumbart, Nicholas Noinaj

Recent studies have demonstrated BamA, the central component of the β-barrel assembly machinery (BAM), as an important therapeutic target to combat infections caused by Acinetobacter baumannii and other Gram-negative pathogens. Homology modeling indicates BamA in A. baumannii consists of five polypeptide transport-associated (POTRA) domains and a β-barrel membrane domain. We characterized the POTRA domains of BamA from A. baumannii in solution using size-exclusion chromatography small angle X-ray scattering (SEC-SAXS) analysis and determined crystal structures in two conformational states that are drastically different than those previously observed in BamA from other bacteria, indicating that the POTRA domains are even more conformationally dynamic than has been observed previously. Molecular dynamics simulations of the POTRA domains from A. baumannii and Escherichia coli allowed us to identify key structural features that contribute to the observed novel states. Together, these studies expand on our current understanding of the conformational plasticity within BamA across differing bacterial species.

最近的研究表明,鲍曼不动杆菌(Acinetobacter baumannii)和其他革兰氏阴性病原体引起的感染的一个重要治疗靶点--β-管组装机制(BAM)的核心成分 BamA。同源建模显示,鲍曼不动杆菌中的 BamA 由五个多肽转运相关(POTRA)结构域和一个 β 管膜结构域组成。我们利用尺寸排阻色谱小角 X 射线散射(SEC-SAXS)分析鉴定了鲍曼不动杆菌 BamA 的 POTRA 结构域在溶液中的特征,并确定了两种构象状态下的晶体结构,这两种构象状态与以前在其他细菌的 BamA 中观察到的构象状态截然不同,表明 POTRA 结构域的构象动态性比以前观察到的更强。通过对鲍曼不动杆菌和大肠杆菌的 POTRA 结构域进行分子动力学模拟,我们确定了导致观察到的新状态的关键结构特征。这些研究共同拓展了我们目前对不同细菌物种中 BamA 构象可塑性的理解。
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引用次数: 0
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