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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
Crystal structure of lipase from Pseudomonas aeruginosa reveals an unusual catalytic triad conformation. 铜绿假单胞菌脂肪酶的晶体结构揭示了不寻常的催化三元构象。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 Epub Date: 2024-07-17 DOI: 10.1016/j.str.2024.06.014
Gang Xu, Hua Guo, Zhonglang Yu, Shulin Wang, Dandan Shen, Lirong Yang, Jianping Wu, Binbin Chen, Haoran Yu

The Pseudomonas aeruginosa lipase PaL catalyzes the stereoselective hydrolysis of menthyl propionate to produce L-menthol. The lack of a three-dimensional structure of PaL has so far prevented a detailed understanding of its stereoselective reaction mechanism. Here, the crystal structure of PaL was determined at a resolution of 1.80 Å by single-wavelength anomalous diffraction. In the apo-PaL structure, the catalytic His302 is located in a long loop on the surface that is solvent exposed. His302 is distant from the other two catalytic residues, Asp274 and Ser164. This configuration of catalytic residues is unusual for lipases. Using metadynamics simulations, we observed that the enzyme undergoes a significant conformational change upon ligand binding. We also explored the catalytic and stereoselectivity mechanisms of PaL by all-atom molecular dynamics simulations. These findings could guide the engineering of PaL with an improved diastereoselectivity for L-menthol production.

铜绿假单胞菌脂肪酶 PaL 可催化丙酸薄荷酯的立体选择性水解,生成 L-薄荷醇。迄今为止,由于缺乏 PaL 的三维结构,人们无法详细了解其立体选择性反应机制。在此,我们通过单波长反常衍射测定了 PaL 的晶体结构,其分辨率为 1.80 Å。在apo-PaL结构中,催化剂His302位于表面的一个长环上,该环暴露在溶剂中。His302 与另外两个催化残基 Asp274 和 Ser164 相距甚远。这种催化残基的构型在脂肪酶中并不多见。通过元动力学模拟,我们观察到该酶在与配体结合后发生了显著的构象变化。我们还通过全原子分子动力学模拟探索了 PaL 的催化和立体选择性机制。这些发现可以指导人们设计出具有更好非对映选择性的 PaL,用于生产 L-薄荷醇。
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引用次数: 0
Antiterminator LoaP loads onto RNA to chase a runaway RNA polymerase 反终结者 LoaP 加载到 RNA 上,追逐失控的 RNA 聚合酶
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.str.2024.07.024
Bing Wang, Irina Artsimovitch

In this issue of Structure, Elghondakly et al.1 present the crystal structure of Thermoanaerobacter pseudethanolicus antiterminator LoaP, a member of a ubiquitous family of NusG transcription factors, bound to its target, a dfn RNA hairpin. LoaP uses RNA as a recognition determinant, which is unique among NusG paralogs and makes unusual contacts in the major groove of the RNA.

在本期《结构》杂志上,Elghondakly 等人1 发现了假乙醇嗜热杆菌(Thermoanaerobacter pseudethanolicus)反终结因子 LoaP 与其目标(dfn RNA 发夹)结合的晶体结构,LoaP 是无处不在的 NusG 转录因子家族的一员。LoaP 使用 RNA 作为识别决定因子,这在 NusG 旁系亲属中是独一无二的,并且在 RNA 的主要沟槽中进行不寻常的接触。
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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
Structural review of SARS-CoV-2 antiviral targets SARS-CoV-2 抗病毒靶标的结构回顾
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.str.2024.08.005
Wen Cui, Yinkai Duan, Yan Gao, Wei Wang, Haitao Yang

The coronavirus disease 2019 (COVID-19), the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), represents the most disastrous infectious disease pandemic of the past century. As a member of the Betacoronavirus genus, the SARS-CoV-2 genome encodes a total of 29 proteins. The spike protein, RNA-dependent RNA polymerase, and proteases play crucial roles in the virus replication process and are promising targets for drug development. In recent years, structural studies of these viral proteins and of their complexes with antibodies and inhibitors have provided valuable insights into their functions and laid a solid foundation for drug development. In this review, we summarize the structural features of these proteins and discuss recent progress in research regarding therapeutic development, highlighting mechanistically representative molecules and those that have already been approved or are under clinical investigation.

冠状病毒病 2019(COVID-19)是由严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)引起的疾病,是上个世纪最具灾难性的传染病大流行。作为 Betacoronavirus 属的一员,SARS-CoV-2 基因组共编码 29 种蛋白质。尖峰蛋白、RNA 依赖性 RNA 聚合酶和蛋白酶在病毒复制过程中起着至关重要的作用,是很有希望的药物开发目标。近年来,对这些病毒蛋白及其与抗体和抑制剂复合物的结构研究为了解其功能提供了宝贵的信息,为药物开发奠定了坚实的基础。在这篇综述中,我们总结了这些蛋白质的结构特征,并讨论了有关治疗开发的最新研究进展,重点介绍了在机理上具有代表性的分子以及那些已经获得批准或正在进行临床研究的分子。
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引用次数: 0
Binding of steroid substrates reveals the key to the productive transition of the cytochrome P450 OleP. 类固醇底物的结合揭示了细胞色素 P450 OleP 生产转换的关键。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 Epub Date: 2024-07-05 DOI: 10.1016/j.str.2024.06.005
Antonella Costanzo, Francesca Fata, Ida Freda, Maria Laura De Sciscio, Elena Gugole, Giovanni Bulfaro, Matteo Di Renzo, Luca Barbizzi, Cécile Exertier, Giacomo Parisi, Marco D'Abramo, Beatrice Vallone, Carmelinda Savino, Linda Celeste Montemiglio

OleP is a bacterial cytochrome P450 involved in oleandomycin biosynthesis as it catalyzes regioselective epoxidation on macrolide intermediates. OleP has recently been reported to convert lithocholic acid (LCA) into murideoxycholic acid through a highly regioselective reaction and to unspecifically hydroxylate testosterone (TES). Since LCA and TES mainly differ by the substituent group at the C17, here we used X-ray crystallography, equilibrium binding assays, and molecular dynamics simulations to investigate the molecular basis of the diverse reactivity observed with the two steroids. We found that the differences in the structure of TES and LCA affect the capability of these molecules to directly form hydrogen bonds with N-terminal residues of OleP internal helix I. The establishment of these contacts, by promoting the bending of helix I, fosters an efficient trigger of the open-to-closed structural transition that occurs upon substrate binding to OleP and contributes to the selectivity of the subsequent monooxygenation reaction.

OleP 是一种细菌细胞色素 P450,参与油霉素的生物合成,催化大环内酯中间体的区域选择性环氧化反应。最近有报道称,OleP 可通过高区域选择性反应将石胆酸(LCA)转化为鼠去氧胆酸,并对睾酮(TES)进行非特异性羟化。由于 LCA 和 TES 的主要区别在于 C17 上的取代基,因此我们在此使用 X 射线晶体学、平衡结合试验和分子动力学模拟来研究观察到的这两种类固醇的不同反应性的分子基础。我们发现,TES 和 LCA 结构的差异影响了这些分子与 OleP 内部螺旋 I 的 N 端残基直接形成氢键的能力。这些接触的建立促进了螺旋 I 的弯曲,从而有效地触发了底物与 OleP 结合后发生的从开放到封闭的结构转变,并提高了后续单氧反应的选择性。
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引用次数: 0
RNA dynamics from experimental and computational approaches 从实验和计算方法看 RNA 动力学
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-05 DOI: 10.1016/j.str.2024.07.019
Giovanni Bussi, Massimiliano Bonomi, Paraskevi Gkeka, Michael Sattler, Hashim M. Al-Hashimi, Pascal Auffinger, Maria Duca, Yann Foricher, Danny Incarnato, Alisha N. Jones, Serdal Kirmizialtin, Miroslav Krepl, Modesto Orozco, Giulia Palermo, Samuela Pasquali, Loïc Salmon, Harald Schwalbe, Eric Westhof, Martin Zacharias

Conformational dynamics is crucial for the biological function of RNA molecules and for their potential as therapeutic targets. This meeting report outlines key “take-home” messages that emerged from the presentations and discussions during the CECAM workshop “RNA dynamics from experimental and computational approaches” in Paris, June 26–28, 2023.

构象动力学对 RNA 分子的生物功能及其作为治疗靶点的潜力至关重要。本会议报告概述了 2023 年 6 月 26-28 日在巴黎举行的 CECAM "从实验和计算方法看 RNA 动态 "研讨会上的发言和讨论所产生的主要 "收获"。
{"title":"RNA dynamics from experimental and computational approaches","authors":"Giovanni Bussi, Massimiliano Bonomi, Paraskevi Gkeka, Michael Sattler, Hashim M. Al-Hashimi, Pascal Auffinger, Maria Duca, Yann Foricher, Danny Incarnato, Alisha N. Jones, Serdal Kirmizialtin, Miroslav Krepl, Modesto Orozco, Giulia Palermo, Samuela Pasquali, Loïc Salmon, Harald Schwalbe, Eric Westhof, Martin Zacharias","doi":"10.1016/j.str.2024.07.019","DOIUrl":"https://doi.org/10.1016/j.str.2024.07.019","url":null,"abstract":"<p>Conformational dynamics is crucial for the biological function of RNA molecules and for their potential as therapeutic targets. This meeting report outlines key “take-home” messages that emerged from the presentations and discussions during the CECAM workshop “RNA dynamics from experimental and computational approaches” in Paris, June 26–28, 2023.</p>","PeriodicalId":22168,"journal":{"name":"Structure","volume":"11 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138206","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
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