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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。
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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
Rewiring protein binding specificity in paralogous DRG/DFRP complexes 重构同类 DRG/DFRP 复合物中的蛋白质结合特异性
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-13 DOI: 10.1016/j.str.2024.08.012
Christian A.E. Westrip, Stephen J. Smerdon, Mathew L. Coleman

Eukaryotes have two paralogous developmentally regulated GTP-binding (DRG) proteins: DRG1 and DRG2, both of which have a conserved binding partner called DRG family regulatory protein 1 and 2 (DFRP1 and DFRP2), respectively. DFRPs are important for the function of DRGs and interact with their respective DRG via a conserved region called the DFRP domain. Despite being highly similar, DRG1 and DRG2 have strict binding specificity for their respective DFRP. Using AlphaFold generated structure models of the human DRG/DFRP complexes, we have biochemically characterized their interactions and identified interface residues involved in determining specificity. This analysis revealed that as few as five mutations in DRG1 can switch binding from DFRP1 to DFRP2. Moreover, while DFRP1 binding confers increased stability and GTPase activity to DRG1, DFRP2 binding only supports increased stability. Overall, this work provides new insight into the structural determinants responsible for the binding specificities of the DRG/DFRP complexes.

真核生物有两种同源的发育调控 GTP 结合蛋白(DRG):DRG1和DRG2都有一个保守的结合伙伴,分别称为DRG家族调控蛋白1和2(DFRP1和DFRP2)。DFRP 对 DRG 的功能非常重要,它们通过一个名为 DFRP 结构域的保守区域与各自的 DRG 相互作用。尽管 DRG1 和 DRG2 高度相似,但它们与各自的 DFRP 有严格的结合特异性。利用 AlphaFold 生成的人类 DRG/DFRP 复合物结构模型,我们对它们的相互作用进行了生化鉴定,并确定了决定特异性的界面残基。这项分析表明,DRG1 中只要有五个突变就能将 DFRP1 的结合转换为 DFRP2 的结合。此外,当 DFRP1 的结合赋予 DRG1 更高的稳定性和 GTPase 活性时,DFRP2 的结合只支持更高的稳定性。总之,这项研究为我们提供了有关 DRG/DFRP 复合物结合特异性的结构决定因素的新见解。
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引用次数: 0
Structural organization of pyruvate: ferredoxin oxidoreductase from the methanogenic archaeon Methanosarcina acetivorans 产甲烷古菌 Methanosarcina acetivorans 的丙酮酸铁氧还蛋白氧化还原酶的结构组织
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-11 DOI: 10.1016/j.str.2024.08.011
Matteo Cossu, Daniel Catlin, Sean J. Elliott, William W. Metcalf, Satish K. Nair

Enzymes of the 2-oxoacid:ferredoxin oxidoreductase (OFOR) superfamily catalyze the reversible oxidation of 2-oxoacids to acyl-coenzyme A esters and carbon dioxide (CO2)using ferredoxin or flavodoxin as the redox partner. Although members of the family share primary sequence identity, a variety of domain and subunit arrangements are known. Here, we characterize the structure of a four-subunit family member: the pyruvate:ferredoxin oxidoreductase (PFOR) from the methane producing archaeon Methanosarcina acetivorans (MaPFOR). The 1.92 Å resolution crystal structure of MaPFOR shows a protein fold like those of single- or two-subunit PFORs that function in 2-oxoacid oxidation, including the location of the requisite thiamine pyrophosphate (TPP), and three [4Fe-4S] clusters. Of note, MaPFOR typically functions in the CO2 reductive direction, and structural comparisons to the pyruvate oxidizing PFORs show subtle differences in several regions of catalytical relevance. These studies provide a framework that may shed light on the biochemical mechanisms used to facilitate reductive pyruvate synthesis.

2-oxoacid:ferredoxin 氧化还原酶(OFOR)超家族的酶以 ferredoxin 或 flavodoxin 为氧化还原伴侣,催化 2-oxoacid 可逆氧化成酰基辅酶 A 酯和二氧化碳(CO2)。虽然该家族成员的主要序列相同,但已知的结构域和亚基排列却多种多样。在这里,我们描述了一个四亚基家族成员的结构:产甲烷古菌 Methanosarcina acetivorans(MaPFOR)的丙酮酸:铁氧还蛋白氧化还原酶(PFOR)。MaPFOR 的 1.92 Å 分辨率晶体结构显示,其蛋白质折叠结构与那些在 2-氧代酸氧化过程中起作用的单亚基或双亚基 PFOR 类似,包括必要的焦磷酸硫胺(TPP)和三个 [4Fe-4S] 簇的位置。值得注意的是,MaPFOR 通常在二氧化碳还原方向发挥功能,而且与丙酮酸氧化型 PFOR 的结构比较显示,两者在催化相关的几个区域存在微妙差异。这些研究提供了一个框架,可以揭示促进还原性丙酮酸合成的生化机制。
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引用次数: 0
Ping, pong, and freeze: Structural insights into the inhibition of ceramide synthase by Fumonisin B1 乒乓球和冷冻:伏马菌素 B1 对神经酰胺合成酶抑制作用的结构性启示
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.str.2024.08.010
Kexin Hu, Yu Cao

Fumonisin B1 (FB1) targets sphingolipid biosynthesis, inhibiting ceramide synthases. In this issue of Structure, Zhang et al.1 determined the cryoelectron microscopic structures of yeast ceramide synthase in complex with FB1 and its acylated derivative, acyl-FB1, revealing a two-step “ping-pong” mechanism for the N-acylation of FB1 and how it inhibits ceramide synthase.

伏马菌素 B1(FB1)以鞘脂生物合成为目标,抑制神经酰胺合成酶。在本期《结构》杂志上,Zhang 等人1测定了酵母神经酰胺合成酶与 FB1 及其酰化衍生物酰基-FB1 复合物的冷冻电镜结构,揭示了 FB1 N-酰化的两步 "乒乓 "机制及其如何抑制神经酰胺合成酶。
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引用次数: 0
Expanding the insect defensin landscape 扩大昆虫防御素范围
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.str.2024.08.009
Krishnakoli Adhikary, Sébastien F. Poget

In this issue of Structure, Walker et al.1 determined the NMR structure of a recently discovered defensin, Pp19, from the venom of an assassin bug. This peptide adopts an α-defensin-like structure, which had not been observed in insects before. Unlike mammalian α-defensins, which are generally antimicrobial, Pp19 has insecticidal activity.

在本期《结构》杂志上,Walker 等人1测定了最近从一种刺蝽毒液中发现的防御素 Pp19 的核磁共振结构。这种肽具有类似α-防御素的结构,以前从未在昆虫中观察到过。哺乳动物的α防御素通常具有抗菌作用,而Pp19则不同,它具有杀虫活性。
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引用次数: 0
Ordering the disordered 为无序者排序
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.str.2024.08.004
Sarah Shammas, Gabriella Heller, Alaji Bah, Emmanouela Filippidi, Alex Holehouse, Miao Yu, Janin Lautenschläger

In this Voices article, we introduce seven impressive young group leaders that presented their work at the recent Gordon Research Conference “Biophysics and biology of intrinsically disordered proteins” in Les Diablerets, Switzerland. We asked them to tell us more about their careers and their fascinating research on proteins that do not adopt a single-folded structure.

在这篇 "声音 "文章中,我们介绍了七位令人印象深刻的年轻组长,他们在最近于瑞士Les Diablerets举行的戈登研究会议 "固有无序蛋白的生物物理学和生物学 "上展示了自己的研究成果。我们请他们向我们详细介绍了他们的职业生涯以及他们对非单一折叠结构蛋白质的精彩研究。
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引用次数: 0
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