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Transcription start site choice regulates HIV-1 RNA conformation and function 转录起始位点的选择调节 HIV-1 RNA 的构象和功能。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.sbi.2024.102896

HIV-1, the causative agent of AIDS, is a retrovirus that packages two copies of unspliced viral RNA as a dimer into newly budding virions. The unspliced viral RNA also serves as an mRNA template for translation of two polyproteins. Recent studies suggest that the fate of the viral RNA (genome or mRNA) is determined at the level of transcription. RNA polymerase II uses heterogeneous transcription start sites to generate major transcripts that differ in only two guanosines at the 5ʹ end. Remarkably, this two-nucleotide difference is sufficient to alter the structure of the 5ʹ-untranslated region and generate two pools of RNA with distinct functions. The presence of both RNA species is needed for optimal viral replication and fitness.

艾滋病的病原体 HIV-1 是一种逆转录病毒,它将两份未拼接的病毒 RNA 作为二聚体打包到新萌发的病毒中。未拼接的病毒 RNA 也是翻译两种多聚蛋白的 mRNA 模板。最新研究表明,病毒 RNA(基因组或 mRNA)的命运取决于转录水平。RNA 聚合酶 II 利用异质转录起始位点产生主要转录本,这些转录本的 5' 端只有两个鸟苷酸不同。值得注意的是,这两个核苷酸的差异足以改变 5'-非翻译区的结构,并产生两个具有不同功能的 RNA 池。这两种 RNA 的存在对病毒的最佳复制和适应性都是必需的。
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引用次数: 0
Structural and biophysical dissection of RNA conformational ensembles RNA 构象组合的结构和生物物理剖析
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-14 DOI: 10.1016/j.sbi.2024.102908

RNA's ability to form and interconvert between multiple secondary and tertiary structures is critical to its functional versatility and the traditional view of RNA structures as static entities has shifted towards understanding them as dynamic conformational ensembles. In this review we discuss RNA structural ensembles and their dynamics, highlighting the concept of conformational energy landscapes as a unifying framework for understanding RNA processes such as folding, misfolding, conformational changes, and complex formation. Ongoing advancements in cryo-electron microscopy and chemical probing techniques are significantly enhancing our ability to investigate multiple structures adopted by conformationally dynamic RNAs, while traditional methods such as nuclear magnetic resonance spectroscopy continue to play a crucial role in providing high-resolution, quantitative spatial and temporal information. We discuss how these methods, when used synergistically, can provide a comprehensive understanding of RNA conformational ensembles, offering new insights into their regulatory functions.

RNA 在多种二级和三级结构之间形成和相互转换的能力对其功能的多样性至关重要,而将 RNA 结构视为静态实体的传统观点已转向将其理解为动态构象组合。在这篇综述中,我们将讨论 RNA 结构组合及其动力学,强调构象能谱的概念是理解折叠、错误折叠、构象变化和复合物形成等 RNA 过程的统一框架。低温电子显微镜和化学探测技术的不断进步大大提高了我们研究构象动态 RNA 所采用的多种结构的能力,而核磁共振光谱等传统方法在提供高分辨率、定量的空间和时间信息方面继续发挥着至关重要的作用。我们将讨论这些方法如何协同使用,从而全面了解 RNA 的构象组合,为了解其调控功能提供新的视角。
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引用次数: 0
The role of intrinsic protein disorder in regulation of cyclin-dependent kinases 内在蛋白质紊乱在周期蛋白依赖性激酶调控中的作用
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-13 DOI: 10.1016/j.sbi.2024.102906

While the structure/function paradigm for folded domains was established decades ago, our understanding of how intrinsically disordered regions (IDRs) contribute to biological function is still evolving. IDRs exist as conformational ensembles that can range from highly compact to highly extended depending on their sequence composition. IDR sequences are less conserved than those of folded domains, but often display short, conserved segments termed short linear motifs (SLiMs), that often mediate protein–protein interactions and are often regulated by posttranslational modifications, giving rise to complex functionality when multiple, differently regulated SLiMs are combined. This combinatorial functionality was associated with signaling and regulation soon after IDRs were first recognized as functional elements within proteins. Here, we discuss roles for disorder in proteins that regulate cyclin-dependent kinases, the master timekeepers of the eukaryotic cell cycle. We illustrate the importance of intrinsic flexibility in the transmission of regulatory signals by these entirely disordered proteins.

虽然折叠结构域的结构/功能范式早在几十年前就已确立,但我们对固有无序区(IDR)如何促进生物功能的认识仍在不断发展。IDR以构象组合的形式存在,根据其序列组成,可以从高度紧凑到高度扩展不等。与折叠结构域相比,IDR 序列的保守性较低,但通常显示出短而保守的片段,这些片段被称为短线性母题(SLiMs),通常介导蛋白质与蛋白质之间的相互作用,并经常受到翻译后修饰的调控,当多个不同调控的 SLiMs 组合在一起时,就会产生复杂的功能。在 IDR 首次被认为是蛋白质内的功能元素后不久,这种组合功能就与信号传递和调控联系在了一起。在这里,我们讨论了调节细胞周期蛋白依赖性激酶(真核细胞周期的主要计时者)的蛋白质中的紊乱作用。我们说明了这些完全无序的蛋白质在传递调控信号时内在灵活性的重要性。
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引用次数: 0
Structure-based approaches in synthetic lethality strategies 基于结构的合成致死策略
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.sbi.2024.102895

Evolution has fostered robust DNA damage response (DDR) mechanisms to combat DNA lesions. However, disruptions in this intricate machinery can render cells overly reliant on the remaining functional but often less accurate DNA repair pathways. This increased dependence on error-prone pathways may result in improper repair and the accumulation of mutations, fostering genomic instability and facilitating the uncontrolled cell proliferation characteristic of cancer initiation and progression. Strategies based on the concept of synthetic lethality (SL) leverage the inherent genomic instability of cancer cells by targeting alternative pathways, thereby inducing selective death of cancer cells. This review emphasizes recent advancements in structural investigations of pivotal SL targets. The significant contribution of structure-based methodologies to SL research underscores their potential impact in characterizing the growing number of SL targets, largely due to advances in next-generation sequencing. Harnessing these approaches is essential for advancing the development of precise and personalized SL therapeutic strategies.

进化促进了强大的 DNA 损伤应答(DDR)机制,以应对 DNA 病变。然而,这一复杂机制的破坏会使细胞过度依赖剩余的功能性DNA修复途径,但其准确性往往较低。这种对易出错途径的依赖性增加,可能会导致修复不当和突变积累,加剧基因组的不稳定性,促进癌症发生和发展过程中特有的不受控制的细胞增殖。基于合成致死(SL)概念的策略通过靶向替代途径,利用癌细胞固有的基因组不稳定性,从而诱导癌细胞选择性死亡。本综述强调了最近在关键合成致死靶点结构研究方面取得的进展。基于结构的方法对 SL 研究的重大贡献凸显了它们在表征日益增多的 SL 靶点方面的潜在影响,这主要归功于下一代测序技术的进步。利用这些方法对于推动精准和个性化 SL 治疗策略的发展至关重要。
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引用次数: 0
Challenges, advances, and opportunities in RNA structural biology by Cryo-EM 利用低温电子显微镜研究 RNA 结构生物学的挑战、进展和机遇。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-08 DOI: 10.1016/j.sbi.2024.102894

RNAs are remarkably versatile molecules that can fold into intricate three-dimensional (3D) structures to perform diverse cellular and viral functions. Despite their biological importance, relatively few RNA 3D structures have been solved, and our understanding of RNA structure–function relationships remains in its infancy. This limitation partly arises from challenges posed by RNA's complex conformational landscape, characterized by structural flexibility, formation of multiple states, and a propensity to misfold. Recently, cryo-electron microscopy (cryo-EM) has emerged as a powerful tool for the visualization of conformationally dynamic RNA-only 3D structures. However, RNA's characteristics continue to pose challenges. We discuss experimental methods developed to overcome these hurdles, including the engineering of modular modifications that facilitate the visualization of small RNAs, improve particle alignment, and validate structural models.

RNA 是一种用途极为广泛的分子,可以折叠成错综复杂的三维(3D)结构,从而发挥多种细胞和病毒功能。尽管 RNA 具有重要的生物学意义,但已解决的 RNA 三维结构却相对较少,而且我们对 RNA 结构-功能关系的理解仍处于起步阶段。这种局限性的部分原因是 RNA 复杂的构象格局所带来的挑战,其特点是结构灵活、可形成多种状态以及容易折叠错误。最近,低温电子显微镜(cryo-EM)已成为可视化构象动态纯 RNA 三维结构的有力工具。然而,RNA 的特性继续带来挑战。我们讨论了为克服这些障碍而开发的实验方法,包括促进小 RNA 可视化、改善粒子配准和验证结构模型的模块化修饰工程。
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引用次数: 0
Structures and compositional dynamics of Mediator in transcription regulation 转录调控中 Mediator 的结构和组成动态。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-26 DOI: 10.1016/j.sbi.2024.102892

The eukaryotic Mediator, comprising a large Core (cMED) and a dissociable CDK8 kinase module (CKM), functions as a critical coregulator during RNA polymerase II (RNAPII) transcription. cMED recruits RNAPII and facilitates the assembly of the pre-initiation complex (PIC) at promoters. In contrast, CKM prevents RNAPII binding to cMED while simultaneously exerting positive or negative influence on gene transcription through its kinase function. Recent structural studies on cMED and CKM have revealed their intricate architectures and subunit interactions. Here, we explore these structures, providing a comprehensive insight into Mediator (cMED-CKM) architecture and its potential mechanism in regulating RNAPII transcription. Additionally, we discuss the remaining puzzles that require further investigation to fully understand how cMED coordinates with CKM to regulate transcription in various events.

真核生物 Mediator 由一个大核心(cMED)和一个可分离的 CDK8 激酶模块(CKM)组成,在 RNA 聚合酶 II(RNAPII)转录过程中起着关键核心调节器的作用。相反,CKM 可阻止 RNAPII 与 cMED 结合,同时通过其激酶功能对基因转录产生积极或消极的影响。最近对 cMED 和 CKM 的结构研究揭示了它们错综复杂的结构和亚基相互作用。在此,我们将探讨这些结构,全面了解 Mediator(cMED-CKM)的结构及其调控 RNAPII 转录的潜在机制。此外,我们还讨论了仍需进一步研究的难题,以全面了解 cMED 如何与 CKM 相互协调,在各种事件中调控转录。
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引用次数: 0
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

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

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

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

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
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Current opinion in structural biology
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