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Conformational dynamics of SARS-CoV-2 Omicron spike trimers during fusion activation at single molecule resolution 以单分子分辨率观察 SARS-CoV-2 Omicron 穗状三聚体在融合激活过程中的构象动态
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 DOI: 10.1016/j.str.2024.09.008
Shuvankar Dey, Purba Pahari, Srija Mukherjee, James B. Munro, Dibyendu Kumar Das
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron entry involves spike (S) glycoprotein-mediated fusion of viral and late endosomal membranes. Here, using single-molecule Förster resonance energy transfer (sm-FRET) imaging and biochemical measurements, we directly visualized conformational changes of individual spike trimers on the surface of SARS-CoV-2 Omicron pseudovirions during fusion activation. We observed that the S2 domain of the Omicron spike is a dynamic fusion machine. S2 reversibly interchanges between the pre-fusion conformation and two previously undescribed intermediate conformations. Acidic pH shifts the conformational equilibrium of S2 toward an intermediate conformation and promotes the membrane hemi-fusion reaction. Moreover, we captured conformational reversibility in the S2 domain, which suggests that spike can protect itself from pre-triggering. Furthermore, we determined that Ca2+ directly promotes the S2 conformational change from an intermediate conformation to post-fusion conformation. In the presence of a target membrane, low pH and Ca2+ stimulate the irreversible transition to S2 post-fusion state and promote membrane fusion.
严重急性呼吸系统综合征冠状病毒 2(SARS-CoV-2)奥米克隆的进入涉及尖峰(S)糖蛋白介导的病毒膜和晚期内体膜的融合。在这里,我们利用单分子佛尔斯特共振能量转移(sm-FRET)成像和生化测量,直接观察了SARS-CoV-2 Omicron假病毒表面单个尖峰三聚体在融合激活过程中的构象变化。我们观察到,Omicron 穗状病毒的 S2 结构域是一个动态的融合机器。S2 可逆地在融合前构象和两种以前未曾描述过的中间构象之间互换。酸性 pH 会使 S2 的构象平衡转向中间构象,并促进膜半融合反应。此外,我们还捕捉到了 S2 结构域的构象可逆性,这表明尖峰可以保护自己免受预触发的影响。此外,我们还确定 Ca2+ 能直接促进 S2 从中间构象转变为融合后构象。在目标膜存在的情况下,低 pH 值和 Ca2+ 会刺激向 S2 融合后状态的不可逆转变,并促进膜融合。
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引用次数: 0
Crystal structure of blue laccase BP76, a unique termite suicidal defense weapon. 一种独特的白蚁自杀式防御武器--蓝色漆酶 BP76 的晶体结构。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 Epub Date: 2024-08-15 DOI: 10.1016/j.str.2024.07.015
Jana Škerlová, Jiří Brynda, Jan Šobotník, Marek Zákopčaník, Petr Novák, Thomas Bourguignon, David Sillam-Dussès, Pavlína Řezáčová

Aging workers of the termite Neocapritermes taracua can defend their colony by sacrificing themselves by body rupture, mixing the externally stored blue laccase BP76 with hydroquinones to produce a sticky liquid rich in toxic benzoquinones. Here, we describe the crystal structure of BP76 isolated from N. taracua in its native form. The structure reveals several stabilization strategies, including compact folding, glycosylation, and flexible loops with disulfide bridges and tight dimer interface. The remarkable stability of BP76 maintains its catalytic activity in solid state during the lifespan of N. taracua workers, providing old workers with an efficient defensive weapon to protect their colony.

白蚁老龄工蚁(Neocapritermes taracua)可以通过身体破裂牺牲自己来保卫自己的蚁群,将外部储存的蓝色漆酶 BP76 与对苯二酚混合,产生一种富含有毒苯醌的粘性液体。在这里,我们描述了分离自 N. taracua 的原生态 BP76 的晶体结构。该结构揭示了几种稳定策略,包括紧凑折叠、糖基化以及带有二硫桥和紧密二聚体界面的柔性环。BP76 的出色稳定性使其在固态下的催化活性在 N. taracua 工蚁的生命周期中得以维持,为老工蚁提供了保护其群体的有效防御武器。
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引用次数: 0
A BTB extension and ion-binding domain contribute to the pentameric structure and TFAP2A binding of KCTD1. BTB 扩展域和离子结合域有助于 KCTD1 的五聚体结构和 TFAP2A 结合。
IF 4.4 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 Epub Date: 2024-08-26 DOI: 10.1016/j.str.2024.07.023
Daniel M Pinkas, Joshua C Bufton, Alice E Hunt, Charlotte E Manning, William Richardson, Alex N Bullock

KCTD family proteins typically assemble into cullin-RING E3 ligases. KCTD1 is an atypical member that functions instead as a transcriptional repressor. Mutations in KCTD1 cause developmental abnormalities and kidney fibrosis in scalp-ear-nipple syndrome. Here, we present unexpected mechanistic insights from the structure of human KCTD1. Disease-causing mutation P20S maps to an unrecognized extension of the BTB domain that contributes to both its pentameric structure and TFAP2A binding. The C-terminal domain (CTD) shares its fold and pentameric assembly with the GTP cyclohydrolase I feedback regulatory protein (GFRP) despite lacking discernible sequence similarity. Most surprisingly, the KCTD1 CTD establishes a central channel occupied by alternating sodium and iodide ions that restrict TFAP2A dissociation. The elucidation of the structure redefines the KCTD1 BTB domain fold and identifies an unexpected ion-binding site for future study of KCTD1's function in the ectoderm, neural crest, and kidney.

KCTD 家族蛋白通常组装成 cullin-RING E3 连接酶。KCTD1 是一个非典型成员,它的功能是转录抑制因子。KCTD1 基因突变会导致头皮-耳朵-乳头综合征中的发育异常和肾脏纤维化。在这里,我们从人类 KCTD1 的结构中提出了意想不到的机理见解。致病突变 P20S 映射到 BTB 结构域的一个未被识别的延伸部分,该延伸部分有助于其五聚体结构和 TFAP2A 的结合。C 端结构域(CTD)与 GTP 环醇酶 I 反馈调节蛋白(GFRP)具有相同的折叠和五聚体结构,尽管缺乏明显的序列相似性。最令人惊讶的是,KCTD1 CTD 建立了一个由钠离子和碘离子交替占据的中心通道,限制了 TFAP2A 的解离。该结构的阐明重新定义了 KCTD1 BTB 结构域的折叠,并为今后研究 KCTD1 在外胚层、神经嵴和肾脏中的功能确定了一个意想不到的离子结合位点。
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引用次数: 0
Probing hot spots of protein-protein interactions mediated by the safety-belt region of REV7 探测REV7安全带区域介导的蛋白质-蛋白质相互作用热点
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 DOI: 10.1016/j.str.2024.09.007
Radha Charan Dash, Gianluca A. Arianna, Seema M. Patel, Alessandro A. Rizzo, Noah J. Harrahill, Dmitry M. Korzhnev, M. Kyle Hadden
REV7 is a HORMA (Hop1, Rev7, Mad2) family adaptor protein best known as an accessory subunit of the translesion synthesis (TLS) DNA polymerase ζ (Polζ). In this role, REV7 binds REV3, the catalytic subunit of Polζ, by locking REV7-binding motifs (RBMs) in REV3 underneath the REV7 safety-belt loop. The same mechanism is used by REV7 to interact with RBMs from other proteins in DNA damage response (DDR) and mitosis. Because of the importance of REV7 for TLS and other DDR pathways, targeting REV7:RBM protein-protein interactions (PPIs) with small molecules has emerged as a strategy to enhance cancer response to genotoxic chemotherapy. To identify druggable pockets at the REV7:RBM interface, we performed computational analyses of REV7 complexed with several RBM partners. The contributions of different interface regions to REV7:RBM stabilization were corroborated experimentally. These studies provide insights into key intermolecular interactions and establish targetable regions of REV7 for the design of REV7:RBM PPI inhibitors.
REV7是一种HORMA(Hop1、Rev7、Mad2)家族适配蛋白,最著名的作用是作为转子合成(TLS)DNA聚合酶ζ(Polζ)的附属亚基。在扮演这一角色时,REV7 通过将 REV3 中的 REV7 结合基序(RBM)锁定在 REV7 安全带环路下方,从而与 Polζ 的催化亚基 REV3 结合。在 DNA 损伤应答(DDR)和有丝分裂过程中,REV7 也利用同样的机制与其他蛋白质的 RBM 相互作用。由于REV7对TLS和其他DDR途径的重要性,用小分子靶向REV7:RBM蛋白-蛋白相互作用(PPIs)已成为增强癌症对基因毒性化疗反应的一种策略。为了确定REV7:RBM界面上的药物口袋,我们对REV7与几个RBM伙伴的复合物进行了计算分析。实验证实了不同界面区域对 REV7:RBM 稳定性的贡献。这些研究深入揭示了关键的分子间相互作用,并为设计 REV7:RBM PPI 抑制剂确立了 REV7 的靶向区域。
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引用次数: 0
One RING to rule them all: Mind bomb-1 ccRING3 controls Notch signaling 一环定江山心灵炸弹-1 ccRING3 控制 Notch 信号转导
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 DOI: 10.1016/j.str.2024.09.009
Kristen M. Ramsey, Doug Barrick
In this issue of Structure, Cao et al.1 use X-ray crystallography, biochemical, and genetic studies to define the key role of the Mind bomb-1 ccRING3 domain in triggering Notch signaling, and they demonstrate that ccRING3-mediated dimerization is a key step in ligand activation.
在本期《结构》杂志上,Cao 等人1 利用 X 射线晶体学、生物化学和遗传学研究明确了 Mind bomb-1 ccRING3 结构域在触发 Notch 信号转导中的关键作用,并证明 ccRING3 介导的二聚化是配体激活的关键步骤。
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引用次数: 0
Aberrant tau condensates as catalytic microcompartments propel tau fibrillation 作为催化微空腔的畸变 tau 凝聚物推动 tau 纤维化
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 DOI: 10.1016/j.str.2024.09.004
Agustín Mangiarotti, Asima Nayak, Dragomir Milovanovic
In this issue of Structure, Soeda et al.1 employed optogenetic tools and demonstrate that an N-terminal truncation of tau and microtubule-binding deficiency lead to the formation of tau condensates, accelerating its fibrillation.
在本期《结构》杂志上,Soeda 等人1 利用光遗传学工具证明,tau 的 N 端截断和微管结合缺陷会导致 tau 凝聚物的形成,从而加速其纤维化。
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引用次数: 0
First contact(in): The complete structure of contactin 2 第一次接触:接触素 2 的完整结构
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 DOI: 10.1016/j.str.2024.09.003
Lucas M.P. Chataigner, Bert J.C. Janssen
In this issue of Structure, Fan et al.1 report the structure of the full contactin 2 ectodomain, representing the first for the contactin family. The work reveals six immunoglobulin domains are essential for intercellular interactions, explores differences in proposed contactin 2 homodimerization mechanisms, and provides an updated model for contactin 2 organization on and between cells.
在本期《结构》杂志上,Fan 等人1 报告了完整的接触素 2 外结构域的结构,这是接触素家族的首次发现。该研究揭示了六个免疫球蛋白结构域对于细胞间的相互作用至关重要,探讨了所提出的接触素 2 同源二聚化机制的差异,并为细胞内和细胞间的接触素 2 组织提供了一个最新模型。
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引用次数: 0
Ubiquitous ubiquitin: From bacteria to eukaryotes 无处不在的泛素:从细菌到真核生物
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-10-03 DOI: 10.1016/j.str.2024.09.002
Mohit Misra, Ivan Ðikić
In a recent issue of Nature, Chambers et al.1 combined bioinformatics, biochemistry, and X-ray crystallography to uncover the presence of a ubiquitin-like machinery in bacteria, which was believed to be unique to archaea and eukaryotes. This study highlights the prevalence of a ubiquitin-like system in bacteria that was later adopted by the eukaryotes for various purposes such as protein degradation.
在最近一期的《自然》(Nature)杂志上,钱伯斯等人1 结合生物信息学、生物化学和 X 射线晶体学,发现了细菌中存在泛素样机制,而这种机制被认为是古细菌和真核生物所独有的。这项研究强调了类泛素系统在细菌中的普遍存在,这种系统后来被真核生物所采用,用于蛋白质降解等各种用途。
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引用次数: 0
The variable structural flexibility of the Bacillus circulans β-galactosidase isoforms determines their unique functionalities 环状芽孢杆菌 β-半乳糖苷酶异构体的结构灵活性决定了它们的独特功能
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-30 DOI: 10.1016/j.str.2024.09.005
Michaela Hovorková, Barbora Kaščáková, Lucie Petrásková, Petra Havlíčková, Jiří Nováček, Daniel Pinkas, Zdenko Gardian, Vladimír Křen, Pavla Bojarová, Ivana Kutá Smatanová
β-Galactosidase from Bacillus circulans ATCC 31382 (BgaD) is a biotechnologically important enzyme for the synthesis of β-galactooligosaccharides (GOS). Among its four isoforms, isoform A (BgaD-A) has distinct synthetic properties. Here, we present cryoelectron microscopy (cryo-EM) structures of BgaD-A and compare them with the known X-ray crystal structure of isoform D (BgaD-D), revealing substantial structural divergences between the two isoforms. In contrast to BgaD-D, BgaD-A features a flexible Big-4 domain and another enigmatic domain. The newly identified flexible region in BgaD-A is termed as “barrier domain 8,” and serves as a barricade, obstructing the access of longer oligosaccharide substrates into the active site of BgaD-A. The transgalactosylation reactions catalyzed by both isoforms revealed that BgaD-A has a higher selectivity than BgaD-D in the earlier stages of the reaction and is prevailingly directed to shorter galactooligosaccharides. This study improves our understanding of the structural determinants governing β-galactosidase catalysis, with implications for tailored GOS production.
环状芽孢杆菌(Bacillus circulans)ATCC 31382 的 β-半乳糖苷酶(BgaD)是合成 β-半乳寡糖(GOS)的一种重要生物技术酶。在其四种同工酶中,同工酶 A(BgaD-A)具有独特的合成特性。在这里,我们展示了 BgaD-A 的冷冻电子显微镜(cryo-EM)结构,并将其与已知的同工型 D(BgaD-D)的 X 射线晶体结构进行了比较,发现这两种同工型之间存在着很大的结构差异。与 BgaD-D 不同,BgaD-A 具有一个灵活的 Big-4 结构域和另一个神秘的结构域。在 BgaD-A 中新发现的柔性区域被称为 "障碍结构域 8",它起着屏障的作用,阻碍较长的寡糖底物进入 BgaD-A 的活性位点。两种异构体催化的转半乳糖基化反应表明,BgaD-A在反应早期阶段的选择性比BgaD-D高,并且主要针对较短的半乳糖寡糖。这项研究加深了我们对支配β-半乳糖苷酶催化作用的结构决定因素的了解,对定制化 GOS 生产具有重要意义。
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引用次数: 0
Assessing AF2’s ability to predict structural ensembles of proteins 评估 AF2 预测蛋白质结构组合的能力
IF 5.7 2区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-26 DOI: 10.1016/j.str.2024.09.001
Jakob R. Riccabona, Fabian C. Spoendlin, Anna-Lena M. Fischer, Johannes R. Loeffler, Patrick K. Quoika, Timothy P. Jenkins, James A. Ferguson, Eva Smorodina, Andreas H. Laustsen, Victor Greiff, Stefano Forli, Andrew B. Ward, Charlotte M. Deane, Monica L. Fernández-Quintero
Recent breakthroughs in protein structure prediction have enhanced the precision and speed at which protein configurations can be determined. Additionally, molecular dynamics (MD) simulations serve as a crucial tool for capturing the conformational space of proteins, providing valuable insights into their structural fluctuations. However, the scope of MD simulations is often limited by the accessible timescales and the computational resources available, posing challenges to comprehensively exploring protein behaviors. Recently emerging approaches have focused on expanding the capability of AlphaFold2 (AF2) to predict conformational substates of protein. Here, we benchmark the performance of various workflows that have adapted AF2 for ensemble prediction and compare the obtained structures with ensembles obtained from MD simulations and NMR. We provide an overview of the levels of performance and accessible timescales that can currently be achieved with machine learning (ML) based ensemble generation. Significant minima of the free energy surfaces remain undetected.
蛋白质结构预测领域的最新突破提高了确定蛋白质构型的精度和速度。此外,分子动力学(MD)模拟是捕捉蛋白质构象空间的重要工具,为了解蛋白质的结构波动提供了宝贵的见解。然而,分子动力学模拟的范围往往受到可访问时间尺度和可用计算资源的限制,这给全面探索蛋白质行为带来了挑战。最近新出现的方法侧重于扩展 AlphaFold2(AF2)预测蛋白质构象亚态的能力。在此,我们将对采用 AF2 进行集合预测的各种工作流程的性能进行基准测试,并将获得的结构与通过 MD 模拟和 NMR 获得的集合进行比较。我们概述了目前基于机器学习(ML)的集合生成所能达到的性能水平和可访问的时间尺度。自由能表面的重要最小值仍未被发现。
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引用次数: 0
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Structure
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