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Beyond ligand binding: Single molecule observation reveals how riboswitches integrate multiple signals to balance bacterial gene regulation 超越配体结合:单分子观察揭示了核糖开关如何整合多种信号以平衡细菌基因调控。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1016/j.sbi.2024.102893
Adrien Chauvier, Nils G. Walter

Riboswitches are specialized RNA structures that orchestrate gene expression in response to sensing specific metabolite or ion ligands, mostly in bacteria. Upon ligand binding, these conformationally dynamic RNA motifs undergo structural changes that control critical gene expression processes such as transcription termination and translation initiation, thereby enabling cellular homeostasis and adaptation. Because RNA folds rapidly and co-transcriptionally, riboswitches make use of the low complexity of RNA sequences to adopt alternative, transient conformations on the heels of the transcribing RNA polymerase (RNAP), resulting in kinetic partitioning that defines the regulatory outcome. This review summarizes single molecule microscopy evidence that has begun to unveil a sophisticated network of dynamic, kinetically balanced interactions between riboswitch architecture and the gene expression machinery that, together, integrate diverse cellular signals.

核糖开关是一种特异的 RNA 结构,能协调基因表达,以响应特定代谢物或离子配体的感应,主要存在于细菌中。与配体结合后,这些构象动态 RNA 基团会发生结构变化,控制转录终止和翻译启动等关键基因表达过程,从而实现细胞平衡和适应。由于 RNA 的折叠速度很快,而且是共转录的,因此核糖开关利用 RNA 序列的低复杂性,在转录 RNA 聚合酶(RNAP)的跟进下采用替代性的瞬时构象,从而产生动力学分区,确定调控结果。本综述总结了单分子显微镜证据,这些证据已开始揭示核糖开关结构与基因表达机制之间复杂的动态平衡相互作用网络,它们共同整合了各种细胞信号。
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引用次数: 0
Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis 葬礼上的死亡激活死亡酶 MLKL,通过坏死作用杀死细胞。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-25 DOI: 10.1016/j.sbi.2024.102891
Katherine A. Davies , Peter E. Czabotar , James M. Murphy

Necroptosis is a lytic form of programmed cell death implicated in inflammatory pathologies, leading to intense interest in the underlying mechanisms and therapeutic prospects. Here, we review our current structural understanding of how the terminal executioner of the pathway, the dead kinase, mixed lineage kinase domain-like (MLKL), is converted from a dormant to killer form by the upstream regulatory kinase, RIPK3. RIPK3-mediated phosphorylation of MLKL's pseudokinase domain toggles a molecular switch that induces dissociation from a cytoplasmic platform, assembly of MLKL oligomers, and trafficking to the plasma membrane, where activated MLKL accumulates and permeabilises the lipid bilayer to induce cell death. We highlight gaps in mechanistic knowledge of MLKL's activation, how mechanisms diverge between species, and the power of modelling in advancing structural insights.

坏死是程序性细胞死亡的一种溶解形式,与炎症性病变有关,因此人们对其潜在机制和治疗前景产生了浓厚的兴趣。在此,我们回顾了我们目前对这一途径的终端执行者--死亡激酶混合系激酶结构域样(MLKL)如何通过上游调节激酶 RIPK3 从休眠状态转化为杀伤形式的结构性理解。RIPK3 介导的 MLKL 伪激酶结构域磷酸化会触发一个分子开关,诱导 MLKL 从细胞质平台解离,组装成 MLKL 寡聚体,并贩运到质膜,活化的 MLKL 在质膜上聚集并渗透脂质双分子层,从而诱导细胞死亡。我们强调了 MLKL 激活机理知识方面的差距、不同物种之间的机理差异以及建模在推进结构洞察力方面的力量。
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引用次数: 0
Ion-driven rotary membrane motors: From structure to function 离子驱动旋转膜马达:从结构到功能
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-24 DOI: 10.1016/j.sbi.2024.102884
Freddie J.O. Martin, Mònica Santiveri , Haidai Hu , Nicholas M.I. Taylor

Ion-driven membrane motors, essential across all domains of life, convert a gradient of ions across a membrane into rotational energy, facilitating diverse biological processes including ATP synthesis, substrate transport, and bacterial locomotion. Herein, we highlight recent structural advances in the understanding of two classes of ion-driven membrane motors: rotary ATPases and 5:2 motors. The recent structure of the human F-type ATP synthase is emphasised along with the gained structural insight into clinically relevant mutations. Furthermore, we highlight the diverse roles of 5:2 motors and recent mechanistic understanding gained through the resolution of ions in the structure of a sodium-driven motor, combining insights into potential unifying mechanisms of ion selectivity and rotational torque generation in the context of their function as part of complex biological systems.

离子驱动膜马达在生命的各个领域都是必不可少的,它能将膜上的离子梯度转化为旋转能量,促进包括 ATP 合成、底物运输和细菌运动在内的各种生物过程。在此,我们重点介绍在了解两类离子驱动膜马达(旋转 ATP 酶和 5:2 马达)方面取得的最新结构进展。我们重点介绍了人类 F 型 ATP 合成酶的最新结构,以及对临床相关突变的结构认识。此外,我们还强调了 5:2 马达的不同作用,以及通过解析钠驱动马达结构中的离子而获得的最新机理认识,结合作为复杂生物系统一部分的离子选择性和旋转力矩产生的潜在统一机理。
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引用次数: 0
Exploring the conformational landscape of protein kinases 探索蛋白激酶的构象图谱
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-22 DOI: 10.1016/j.sbi.2024.102890
Nancy R. Gough, Charalampos G. Kalodimos

Protein kinases are dynamic enzymes that display complex regulatory mechanisms. Although they possess a structurally conserved catalytic domain, significant conformational dynamics are evident both within a single kinase and across different kinases in the kinome. Here, we highlight methods for exploring this conformational space and its dynamics using kinase domains from ABL1 (Abelson kinase), PKA (protein kinase A), AurA (Aurora A), and PYK2 (proline-rich tyrosine kinase 2) as examples. Such experimental approaches combined with AI-driven methods, such as AlphaFold, will yield discoveries about kinase regulation, the catalytic process, substrate specificity, the effect of disease-associated mutations, as well as new opportunities for structure-based drug design.

蛋白激酶是一种动态酶,具有复杂的调控机制。虽然它们拥有结构上一致的催化结构域,但在单个激酶内部以及激酶组中不同激酶之间都存在明显的构象动态变化。在这里,我们以 ABL1(阿贝尔森激酶)、PKA(蛋白激酶 A)、AurA(极光 A)和PYK2(富脯氨酸酪氨酸激酶 2)的激酶结构域为例,重点介绍探索这种构象空间及其动态的方法。这些实验方法与 AlphaFold 等人工智能驱动的方法相结合,将发现激酶调控、催化过程、底物特异性、疾病相关突变的影响以及基于结构的药物设计的新机遇。
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引用次数: 0
Dynamics in Cre-loxP site-specific recombination Cre-loxP 位点特异性重组的动态变化
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.sbi.2024.102878
Mark P. Foster, Matthew J. Benedek, Tyler D. Billings, Jonathan S. Montgomery

Cre recombinase is a phage-derived enzyme that has found utility for precise manipulation of DNA sequences. Cre recognizes and recombines pairs of loxP sequences characterized by an inverted repeat and asymmetric spacer. Cre cleaves and religates its DNA targets such that error-prone repair pathways are not required to generate intact DNA products. Major obstacles to broader applications are lack of knowledge of how Cre recognizes its targets, and how its activity is controlled. The picture emerging from high resolution methods is that the dynamic properties of both the enzyme and its DNA target are important determinants of its activity in both sequence recognition and DNA cleavage. Improved understanding of the role of dynamics in the key steps along the pathway of Cre-loxP recombination should significantly advance our ability to both redirect Cre to new sequences and to control its DNA cleavage activity in the test tube and in cells.

Cre 重组酶是一种源自噬菌体的酶,可用于精确操作 DNA 序列。Cre 能识别并重组以倒置重复和不对称间隔为特征的成对 loxP 序列。Cre 可裂解和重构其 DNA 目标,这样就不需要通过容易出错的修复途径来生成完整的 DNA 产物。更广泛应用的主要障碍是不了解 Cre 如何识别其靶标以及如何控制其活性。高分辨率方法得出的结论是,酶及其 DNA 靶标的动态特性是决定其序列识别和 DNA 切割活性的重要因素。进一步了解动态特性在 Cre-loxP 重组途径关键步骤中的作用,将大大提高我们在试管和细胞中将 Cre 重定向到新序列以及控制其 DNA 切裂活性的能力。
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引用次数: 0
Biomolecular simulations at the exascale: From drug design to organelles and beyond 超大规模生物分子模拟:从药物设计到细胞器及其他
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.sbi.2024.102887
Vytautas Gapsys , Wojciech Kopec , Dirk Matthes , Bert L. de Groot

The rapid advancement in computational power available for research offers to bring not only quantitative improvements, but also qualitative changes in the field of biomolecular simulation. Here, we review the state of biomolecular dynamics simulations at the threshold to exascale resources becoming available. Both developments in parallel and distributed computing will be discussed, providing a perspective on the state of the art of both. A main focus will be on obtaining binding and conformational free energies, with an outlook to macromolecular complexes and (sub)cellular assemblies.

可用于研究的计算能力的飞速发展不仅为生物分子模拟领域带来了数量上的改进,也带来了质量上的变化。在此,我们回顾了生物分子动力学仿真在超大规模资源可用的临界点上的状况。我们将讨论并行计算和分布式计算的发展,并对这两种技术的现状进行展望。重点将放在获得结合和构象自由能方面,并展望大分子复合物和(亚)细胞组装。
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引用次数: 0
Visualizing RNA structure ensembles by single-molecule correlated chemical probing 通过单分子相关化学探针观察 RNA 结构组合
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-17 DOI: 10.1016/j.sbi.2024.102877
J. Winston Arney , Alain Laederach , Kevin M. Weeks

RNA molecules fold to form complex internal structures. Many of these RNA structures populate ensembles with rheostat-like properties, with each state having a distinct function. Until recently, analysis of RNA structures, especially within cells, was limited to modeling either a single averaged structure or computationally-modeled ensembles. These approaches obscure the intrinsic heterogeneity of many structured RNAs. Single-molecule correlated chemical probing (smCCP) strategies are now making it possible to measure and deconvolute RNA structure ensembles based on efficiently executed chemical probing experiments. Here, we provide an overview of fundamental single-molecule probing principles, review current ensemble deconvolution strategies, and discuss recent applications to diverse biological systems. smCCP is enabling a revolution in understanding how the plasticity of RNA structure is exploited in biological systems to respond to stimuli and alter gene function. The energetics of RNA ensembles are often subtle and a subset can likely be targeted to modulate disease-associated biological processes.

RNA 分子通过折叠形成复杂的内部结构。其中许多 RNA 结构具有类似流变特性的集合,每种状态都有不同的功能。直到最近,对 RNA 结构(尤其是细胞内的 RNA 结构)的分析还局限于单一平均结构建模或计算建模的集合建模。这些方法掩盖了许多结构化 RNA 的内在异质性。现在,单分子相关化学探测(smCCP)策略使基于高效执行的化学探测实验测量和解构 RNA 结构集合成为可能。在此,我们概述了单分子探测的基本原理,回顾了当前的集合解卷积策略,并讨论了最近在不同生物系统中的应用。smCCP 为了解生物系统如何利用 RNA 结构的可塑性来应对刺激和改变基因功能带来了一场革命。RNA 集合的能量学通常是微妙的,其中一部分有可能成为调节疾病相关生物过程的目标。
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引用次数: 0
Diversity of structure and function in Cullin E3 ligases Cullin E3 连接酶结构和功能的多样性
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1016/j.sbi.2024.102879
Calvin P. Lin, Elizabeth A. Komives

The cellular process by which the protein ubiquitin (Ub) is covalently attached to a protein substrate involves Ub activating (E1s) and conjugating enzymes (E2s) that work together with a large variety of E3 ligases that impart substrate specificity. The largest family of E3s is the Cullin-RING ligase (CRL) family which utilizes a wide variety of substrate receptors, adapter proteins, and cooperating ligases. Cryo-electron microscopy (cryoEM) has revealed a wide variety of structures which suggest how Ub transfer occurs. Hydrogen deuterium exchange mass spectrometry (HDXMS) has revealed the role of dynamics and expanded our knowledge of how covalent NEDD8 modification (neddylation) activates the CRLs, particularly by facilitating cooperation with additional RING-between-RING ligases to transfer Ub.

蛋白质泛素(Ub)与蛋白质底物共价连接的细胞过程涉及 Ub 激活酶(E1s)和共轭酶(E2s),它们与大量赋予底物特异性的 E3 连接酶协同工作。最大的 E3 家族是 Cullin-RING 连接酶(CRL)家族,它利用各种底物受体、适配蛋白和合作连接酶。低温电子显微镜(cryoEM)发现了多种结构,这些结构表明了 Ub 转移是如何发生的。氢氘交换质谱(HDXMS)揭示了动力学的作用,并扩展了我们对共价 NEDD8 修饰(neddylation)如何激活 CRLs 的认识,特别是通过促进与其他 RING 之间的连接酶的合作来转移 Ub。
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引用次数: 0
Introducing dysfunctional Protein-Protein Interactome (dfPPI) – A platform for systems-level protein-protein interaction (PPI) dysfunction investigation in disease 引入功能障碍蛋白质-蛋白质相互作用组(dfPPI)--系统级蛋白质-蛋白质相互作用(PPI)功能障碍疾病研究平台
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-13 DOI: 10.1016/j.sbi.2024.102886
Souparna Chakrabarty , Shujuan Wang , Tanaya Roychowdhury , Stephen D. Ginsberg , Gabriela Chiosis

Protein-protein interactions (PPIs) play a crucial role in cellular function and disease manifestation, with dysfunctions in PPI networks providing a direct link between stressors and phenotype. The dysfunctional Protein-Protein Interactome (dfPPI) platform, formerly known as epichaperomics, is a newly developed chemoproteomic method aimed at detecting dynamic changes at the systems level in PPI networks under stressor-induced cellular perturbations within disease states. This review provides an overview of dfPPIs, emphasizing the novel methodology, data analytics, and applications in disease research. dfPPI has applications in cancer research, where it identifies dysfunctions integral to maintaining malignant phenotypes and discovers strategies to enhance the efficacy of current therapies. In neurodegenerative disorders, dfPPI uncovers critical dysfunctions in cellular processes and stressor-specific vulnerabilities. Challenges, including data complexity and the potential for integration with other omics datasets are discussed. The dfPPI platform is a potent tool for dissecting disease systems biology by directly informing on dysfunctions in PPI networks and holds promise for advancing disease identification and therapeutics.

蛋白质-蛋白质相互作用(PPI)在细胞功能和疾病表现中起着至关重要的作用,PPI网络的功能失调是应激源与表型之间的直接联系。功能失调蛋白-蛋白相互作用组(dfPPI)平台以前被称为外显子组学,是一种新开发的化学蛋白组学方法,旨在检测疾病状态下应激物诱导的细胞扰动在 PPI 网络系统水平上的动态变化。本综述概述了 dfPPI,强调了其新颖的方法、数据分析以及在疾病研究中的应用。dfPPI 在癌症研究中得到了应用,它能识别维持恶性表型不可或缺的功能障碍,并发现提高当前疗法疗效的策略。在神经退行性疾病中,dfPPI 发现了细胞过程中的关键功能障碍和压力特异性弱点。会上讨论了所面临的挑战,包括数据的复杂性以及与其他全息数据集整合的潜力。dfPPI 平台通过直接告知 PPI 网络中的功能障碍,是剖析疾病系统生物学的有力工具,有望推动疾病识别和治疗。
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引用次数: 0
The power of computational proteomics platforms to decipher protein-protein interactions 计算蛋白质组学平台破解蛋白质-蛋白质相互作用的威力
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-13 DOI: 10.1016/j.sbi.2024.102882
Mariela González-Avendaño , Joaquín López , Ariela Vergara-Jaque , Oscar Cerda

Adopting computational tools for analyzing extensive biological datasets has profoundly transformed our understanding and interpretation of biological phenomena. Innovative platforms have emerged, providing automated analysis to unravel essential insights about proteins and the complexities of their interactions. These computational advancements align with traditional studies, which employ experimental techniques to discern and quantify physical and functional protein-protein interactions (PPIs). Among these techniques, tandem mass spectrometry is notably recognized for its precision and sensitivity in identifying PPIs. These approaches might serve as important information enabling the identification of PPIs with potential pharmacological significance. This review aims to convey our experience using computational tools for detecting PPI networks and offer an analysis of platforms that facilitate predictions derived from experimental data.

采用计算工具分析大量生物数据集,深刻地改变了我们对生物现象的理解和解释。创新平台不断涌现,它们提供自动分析功能,帮助我们深入了解蛋白质及其相互作用的复杂性。这些计算技术的进步与传统研究相吻合,后者采用实验技术来辨别和量化蛋白质与蛋白质之间的物理和功能性相互作用(PPIs)。在这些技术中,串联质谱法因其识别 PPI 的精确性和灵敏度而备受认可。这些方法可作为鉴定具有潜在药理意义的 PPI 的重要信息。本综述旨在介绍我们使用计算工具检测 PPI 网络的经验,并对有助于从实验数据中得出预测结果的平台进行分析。
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引用次数: 0
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Current opinion in structural biology
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