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Structural and dynamic studies of chromatin by solid-state NMR spectroscopy 利用固态核磁共振光谱对染色质进行结构和动态研究
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-17 DOI: 10.1016/j.sbi.2024.102921

Chromatin is a complex of DNA with histone proteins organized into nucleosomes that regulates genome accessibility and controls transcription, replication and repair by dynamically switching between open and compact states as a function of different parameters including histone post-translational modifications and interactions with chromatin modulators. Continuing advances in structural biology techniques including X-ray crystallography, cryo-electron microscopy and nuclear magnetic resonance (NMR) spectroscopy have facilitated studies of chromatin systems, in spite of challenges posed by their large size and dynamic nature, yielding important functional and mechanistic insights. In this review we highlight recent applications of magic angle spinning solid-state NMR – an emerging technique that is uniquely-suited toward providing atomistic information for rigid and flexible regions within biomacromolecular assemblies – to detailed characterization of structure, conformational dynamics and interactions for histone core and tail domains in condensed nucleosomes and oligonucleosome arrays mimicking chromatin at high densities characteristic of the cellular environment.

染色质是 DNA 与组蛋白组成核小体的复合物,它调节基因组的可及性,并控制转录、复制和修复,通过在开放状态和紧密状态之间动态切换作为不同参数(包括组蛋白翻译后修饰以及与染色质调节剂的相互作用)的函数。结构生物学技术(包括 X 射线晶体学、低温电子显微镜和核磁共振(NMR)光谱)的不断进步促进了染色质系统的研究,尽管其庞大的体积和动态性质带来了挑战,但仍产生了重要的功能和机理见解。在这篇综述中,我们将重点介绍魔角旋转固态核磁共振的最新应用--这种新兴技术非常适合为生物大分子组装体中的刚性和柔性区域提供原子信息--在细胞环境特有的高密度条件下,对凝聚核小体和寡核苷酸阵列中组蛋白核心和尾域的结构、构象动力学和相互作用进行详细表征。
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引用次数: 0
Combining single-molecule and structural studies reveals protein and DNA conformations and assemblies that govern DNA mismatch repair 结合单分子和结构研究揭示支配 DNA 错配修复的蛋白质和 DNA 构象与组合
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-10 DOI: 10.1016/j.sbi.2024.102917

DNA mismatch repair (MMR) requires coordinated sequential actions of multiple proteins during a window of time after the replication apparatus makes an error and before the newly synthesized DNA undergoes chromosome compaction and/or methylation of dGATC sites in some γ-proteobacteria. In this review, we focus on the steps carried out by MutS and MutL homologs that initiate repair. We connect new structural data to early and recent single-molecule FRET and atomic force microscopy (AFM) studies to reveal insights into how signaling within the MMR cascade connects MutS homolog recognition of a mismatch to downstream repair. We present unified models of MMR initiation that account for the differences in the strand discrimination signals between methyl- and non-methyl-directed MMR.

在一些γ-蛋白细菌中,DNA错配修复(MMR)需要在复制装置出错后、新合成的DNA进行染色体压实和/或dGATC位点甲基化之前的一段时间内,由多个蛋白质协调依次进行。在这篇综述中,我们重点讨论了 MutS 和 MutL 同源物启动修复的步骤。我们将新的结构数据与早期和近期的单分子 FRET 和原子力显微镜(AFM)研究联系起来,揭示了 MMR 级联中的信号传递是如何将 MutS 同源物对错配的识别与下游修复联系起来的。我们提出了 MMR 启动的统一模型,这些模型解释了甲基导向和非甲基导向 MMR 之间链分辨信号的差异。
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引用次数: 0
Cryo-EM: A window into the dynamic world of RNA molecules 低温电子显微镜:了解 RNA 分子动态世界的窗口
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-03 DOI: 10.1016/j.sbi.2024.102916

RNAs are critical for complex cellular functions, characterized by their structural versatility and ability to undergo conformational transitions in response to cellular cues. The elusive structures of RNAs are being unraveled with unprecedented clarity, thanks to the technological advancements in structural biology, including nuclear magnetic resonance (NMR), X-ray crystallography, cryo-electron microscopy (cryo-EM) etc. This review focuses on examining the revolutionary impact of cryo-EM on our comprehension of RNA structural dynamics, underscoring the technique's contributions to structural biology and envisioning the future trajectory of this rapidly evolving field.

RNA 对于复杂的细胞功能至关重要,其特点是结构多变,能够根据细胞线索发生构象转变。由于结构生物学技术的进步,包括核磁共振(NMR)、X 射线晶体学、冷冻电镜(cryo-EM)等,难以捉摸的 RNA 结构正以前所未有的清晰度被揭开。这篇综述重点探讨了冷冻电镜技术对我们理解 RNA 结构动力学的革命性影响,强调了该技术对结构生物学的贡献,并展望了这一快速发展领域的未来轨迹。
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引用次数: 0
Influence of membrane on the antigen presentation of the HIV-1 envelope membrane proximal external region (MPER) 膜对 HIV-1 包膜近端外部区域(MPER)抗原呈递的影响
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.sbi.2024.102897

The membrane proximal external region (MPER) of the HIV envelope glycoproteins has generated renewed interest after a recent phase I vaccine trial that presented MPER lipid-peptide epitopes demonstrated promise to elicit a broad neutralization response. The antigenicity of MPER is intimately associated with the membrane, and its presentation relies significantly on the lipid composition. This review brings together recent findings on the influence of membranes on the conformation of MPER and its recognition by broadly neutralizing antibodies. Specifically, the review highlights the importance of properly accounting for the balance between protein–protein and membrane–protein interactions in vaccine design.

最近的一项 I 期疫苗试验显示,呈现 MPER 脂质肽表位的疫苗有望引起广泛的中和反应,这使人们对 HIV 包膜糖蛋白的膜近端外部区域 (MPER) 重新产生了兴趣。MPER 的抗原性与膜密切相关,其表现形式在很大程度上依赖于脂质成分。本综述汇集了有关膜对 MPER 构象的影响及其被广泛中和抗体识别的最新研究成果。具体来说,综述强调了在疫苗设计中适当考虑蛋白质-蛋白质和膜-蛋白质相互作用平衡的重要性。
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引用次数: 0
Untangling the pseudoknots of SARS-CoV-2: Insights into structural heterogeneity and plasticity 解开 SARS-CoV-2 的假结:洞察结构异质性和可塑性
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-21 DOI: 10.1016/j.sbi.2024.102912

Since the onset of the COVID-19 pandemic, one productive area of research has focused on the intricate two- and three-dimensional structures taken on by SARS-CoV-2's RNA genome. These structures control essential viral processes, making them tempting targets for therapeutic intervention. This review focuses on two such structured regions, the frameshift stimulation element (FSE), which controls the translation of viral protein, and the 3′ untranslated region (3′ UTR), which is thought to regulate genome replication. For the FSE, we discuss its canonical pseudoknot's threaded and unthreaded topologies, as well as the diversity of competing two-dimensional structures formed by local and long-distance base pairing. For the 3′ UTR, we review the evidence both for and against the formation of its replication-enabling pseudoknot.

自 COVID-19 大流行以来,一个富有成效的研究领域集中在 SARS-CoV-2 的 RNA 基因组所具有的错综复杂的二维和三维结构上。这些结构控制着病毒的基本过程,使其成为治疗干预的诱人目标。本综述将重点讨论两个这样的结构区域,即控制病毒蛋白质翻译的换帧刺激元件(FSE)和被认为能调节基因组复制的 3′ 非翻译区(3′ UTR)。对于 FSE,我们讨论了其典型的假结的螺纹和非螺纹拓扑结构,以及由局部和长距离碱基配对形成的竞争性二维结构的多样性。对于 3′ UTR,我们回顾了支持和反对形成其复制功能假结的证据。
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引用次数: 0
Dynamic interactions drive early spliceosome assembly 动态相互作用推动早期剪接体的组装
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.sbi.2024.102907

Splicing is a critical processing step during pre-mRNA maturation in eukaryotes. The correct selection of splice sites during the early steps of spliceosome assembly is highly important and crucial for the regulation of alternative splicing. Splice site recognition and alternative splicing depend on cis-regulatory sequence elements in the RNA and trans-acting splicing factors that recognize these elements and crosstalk with the canonical splicing machinery. Structural mechanisms involving early spliceosome complexes are governed by dynamic RNA structures, protein-RNA interactions and conformational flexibility of multidomain RNA binding proteins. Here, we highlight structural studies and integrative structural biology approaches, which provide complementary information from cryo-EM, NMR, small angle scattering, and X-ray crystallography to elucidate mechanisms in the regulation of early spliceosome assembly and quality control, highlighting the role of conformational dynamics.

剪接是真核生物中前 mRNA 成熟过程中的一个关键处理步骤。在剪接体组装的早期步骤中,正确选择剪接位点非常重要,对替代剪接的调控也至关重要。剪接位点的识别和替代剪接取决于 RNA 中的顺式调控序列元件以及识别这些元件并与典型剪接机制发生串联的反式作用剪接因子。涉及早期剪接体复合物的结构机制受动态 RNA 结构、蛋白质-RNA 相互作用以及多域 RNA 结合蛋白构象灵活性的制约。在此,我们重点介绍结构研究和综合结构生物学方法,这些方法提供了低温电子显微镜、核磁共振、小角散射和 X 射线晶体学的互补信息,以阐明早期剪接体组装和质量控制的调控机制,并强调构象动态的作用。
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引用次数: 0
RNA recognition in toll-like receptor signaling 收费样受体信号传递中的 RNA 识别
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.sbi.2024.102913

RNA, either from invading pathogens or within the hosts, is one of the principal PAMPs (pathogen-associated molecular patterns). Toll-like receptors (TLRs) and other receptors of the innate immune system exist that detect immunostimulatory RNA including double and single stranded RNA, and then induce cytokine-mediated antiviral and proinflammatory responses. Recent years have seen remarkable progress in biochemical, immunological, and structural biological studies on TLRs, opening new avenues for TLR signaling. In this review, we highlight our current understanding of RNA- sensing TLRs and discuss the regulatory mechanisms that normally prevent inappropriate responses to self.

来自入侵病原体或宿主体内的 RNA 是主要的 PAMPs(病原体相关分子模式)之一。先天性免疫系统的 Toll 样受体(TLRs)和其他受体能检测到包括双链和单链 RNA 在内的免疫刺激 RNA,然后诱导细胞因子介导的抗病毒和促炎症反应。近年来,有关 TLRs 的生物化学、免疫学和结构生物学研究取得了显著进展,为 TLR 信号转导开辟了新途径。在这篇综述中,我们将重点介绍我们目前对 RNA 传感 TLRs 的理解,并讨论通常防止对自身产生不适当反应的调节机制。
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引用次数: 0
Editorial overview: New concept in drug discovery 编辑综述:药物发现的新概念
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-20 DOI: 10.1016/j.sbi.2024.102911
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引用次数: 0
Supercomputing in the biological sciences: Toward Zettascale and Yottascale simulations 生物科学中的超级计算:迈向 Zettascale 和 Yottascale 模拟。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-19 DOI: 10.1016/j.sbi.2024.102889

Molecular simulations of biological systems tend to be significantly more compute-intensive than those in materials science and astrophysics, due to important contributions of long-range electrostatic forces and large numbers of time steps (>1E9) required. Simulations of biomolecular complexes of microseconds to milliseconds are considered state-of-the-art today. However, these time scales are miniscule in comparison to physiological time scales relevant to molecular machine activity, drug action, and elongation cycles for protein synthesis, RNA synthesis, and DNA synthesis (seconds to days). While an exascale supercomputer has simulated an entire virus for nanoseconds, this supercomputer would need to be 10 billion times faster to simulate that virus for 3 hours of physiological time, demonstrating the insatiable need for computing power. With growing interest in computational drug design from the pharmaceutical sector, the biological sciences are positioned to be an industry driver in computing.

生物系统的分子模拟往往比材料科学和天体物理学的分子模拟计算密集得多,这是因为长程静电力的重要贡献和所需的大量时间步长(>1E9)。微秒到毫秒级的生物分子复合物模拟被认为是当今最先进的模拟。然而,与分子机器活动、药物作用以及蛋白质合成、RNA 合成和 DNA 合成的延长周期(秒到天)相关的生理时间尺度相比,这些时间尺度微不足道。虽然一台超大规模超级计算机已经模拟了纳秒级的整个病毒,但要模拟该病毒 3 小时的生理时间,这台超级计算机的速度还需要快 100 亿倍,这表明了对计算能力的无限需求。随着制药行业对计算药物设计的兴趣与日俱增,生物科学将成为计算行业的驱动力。
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引用次数: 0
Probing protein–DNA interactions and compaction in nanochannels 探测纳米通道中蛋白质与 DNA 的相互作用和压实。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-08-19 DOI: 10.1016/j.sbi.2024.102914

DNA confined to nanofluidic channels with a cross-section from tens to hundreds of nm wide and hundreds of microns long stretches in an equilibrium process free of flow or end tethering. Because DNA is free to move along the channel axis, its extension is exquisitely sensitive to DNA–DNA interactions and the DNA persistence length, as well as the contour length. We discuss how this sensitivity has been used to probe DNA-protein interactions at physiological concentrations of both DNA and proteins.

DNA 被限制在横截面宽几十到几百纳米、长几百微米的纳米流体通道中,在没有流动或末端系链的平衡过程中延伸。由于 DNA 可以沿通道轴线自由移动,因此其延伸对 DNA-DNA 相互作用、DNA 持续长度以及轮廓长度极为敏感。我们将讨论如何利用这种敏感性来探测 DNA 和蛋白质在生理浓度下的相互作用。
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引用次数: 0
期刊
Current opinion in structural biology
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