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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

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

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

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

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
Expanding insights from in situ cryo-EM 扩展原位低温电子显微镜的洞察力
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-11 DOI: 10.1016/j.sbi.2024.102885
Joshua Hutchings , Elizabeth Villa

The combination of cryo-electron tomography and subtomogram analysis affords 3D high-resolution views of biological macromolecules in their native cellular environment, or in situ. Streamlined methods for acquiring and processing these data are advancing attainable resolutions into the realm of drug discovery. Yet regardless of resolution, structure prediction driven by artificial intelligence (AI) combined with subtomogram analysis is becoming powerful in understanding macromolecular assemblies. Automated and AI-assisted data mining is increasingly necessary to cope with the growing wealth of tomography data and to maximize the information obtained from them. Leveraging developments from AI and single-particle analysis could be essential in fulfilling the potential of in situ cryo-EM. Here, we highlight new developments for in situ cryo-EM and the emerging potential for AI in this process.

低温电子断层扫描与子图分析相结合,可提供生物大分子在原生细胞环境或原位的三维高分辨率视图。获取和处理这些数据的简化方法正在将可实现的分辨率推进到药物发现领域。然而,无论分辨率如何,由人工智能(AI)驱动的结构预测与子图分析相结合,在理解大分子组装方面正变得越来越强大。为了应对日益丰富的断层成像数据并最大限度地从中获取信息,自动和人工智能辅助数据挖掘变得越来越必要。利用人工智能和单粒子分析的发展,对于发挥原位冷冻电镜的潜力至关重要。在此,我们将重点介绍原位冷冻电镜的新发展以及人工智能在这一过程中的新兴潜力。
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引用次数: 0
Trends in co-fractionation mass spectrometry: A new gold-standard in global protein interaction network discovery 共分馏质谱的发展趋势:发现全球蛋白质相互作用网络的新黄金标准
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-11 DOI: 10.1016/j.sbi.2024.102880
Raghuveera Kumar Goel , Nazmin Bithi , Andrew Emili

Co-fractionation mass spectrometry (CF-MS) uses biochemical fractionation to isolate and characterize macromolecular complexes from cellular lysates without the need for affinity tagging or capture. In recent years, this has emerged as a powerful technique for elucidating global protein-protein interaction networks in a wide variety of biospecimens. This review highlights the latest advancements in CF-MS experimental workflows including machine learning-guided analyses, for uncovering dynamic and high-resolution protein interaction landscapes with enhanced sensitivity, accuracy and throughput, enabling better biophysical characterization of endogenous protein complexes. By addressing challenges and emergent opportunities in the field, this review underscores the transformative potential of CF-MS in advancing our understanding of functional protein interaction networks in health and disease.

协同分馏质谱法(CF-MS)利用生化分馏技术从细胞裂解物中分离和鉴定大分子复合物,而无需亲和标记或捕获。近年来,这项技术已成为阐明各种生物样本中全球蛋白质-蛋白质相互作用网络的强大技术。本综述重点介绍了 CF-MS 实验工作流程的最新进展,包括机器学习指导的分析,以提高灵敏度、准确性和通量,揭示动态和高分辨率的蛋白质相互作用图谱,从而更好地对内源性蛋白质复合物进行生物物理表征。通过探讨该领域面临的挑战和新出现的机遇,本综述强调了 CF-MS 在促进我们对健康和疾病中蛋白质功能相互作用网络的了解方面所具有的变革潜力。
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引用次数: 0
Pioneer factors: Emerging rules of engagement for transcription factors on chromatinized DNA 先锋因子:染色质 DNA 上转录因子的新规则。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-10 DOI: 10.1016/j.sbi.2024.102875
Manuel Carminati , Luca Vecchia , Lisa Stoos , Nicolas H. Thomä

Pioneering transcription factors (TFs) can drive cell fate changes by binding their DNA motifs in a repressive chromatin environment. Recent structures illustrate emerging rules for nucleosome engagement: TFs distort the nucleosomal DNA to gain access or employ alternative DNA-binding modes with smaller footprints, they preferentially access solvent-exposed motifs near the entry/exit sites, and frequently interact with histones. The extent of TF–histone interactions, in turn, depends on the motif location on the nucleosome, the type of DNA-binding fold, and adjacent domains present. TF–histone interactions can phase TF motifs relative to nucleosomes, and we discuss how these complex and surprisingly diverse interactions between nucleosomes and TFs contribute to function.

先驱转录因子(TF)可通过在抑制性染色质环境中结合其 DNA motifs 来驱动细胞命运的改变。最新的结构说明了新出现的核糖体参与规则:转录因子会扭曲核糖体 DNA 以进入核糖体,或采用足迹较小的其他 DNA 结合模式,它们会优先进入出入位点附近的溶剂暴露基团,并经常与组蛋白相互作用。反过来,TF-组蛋白相互作用的程度取决于核小体上的基调位置、DNA 结合折叠类型以及存在的相邻结构域。TF与组蛋白的相互作用可使TF基团相对于核小体发生相位变化,我们将讨论核小体与TF之间这些复杂而又令人惊奇的相互作用是如何对功能起作用的。
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引用次数: 0
Connecting the dots: Computational network analysis for disease insight and drug repurposing 连接点:通过计算网络分析深入了解疾病和药物再利用。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-10 DOI: 10.1016/j.sbi.2024.102881
Nicoleta Siminea , Eugen Czeizler , Victor-Bogdan Popescu , Ion Petre , Andrei Păun

Network biology is a powerful framework for studying the structure, function, and dynamics of biological systems, offering insights into the balance between health and disease states. The field is seeing rapid progress in all of its aspects: data availability, network synthesis, network analytics, and impactful applications in medicine and drug development. We review the most recent and significant results in network biomedicine, with a focus on the latest data, analytics, software resources, and applications in medicine. We also discuss what in our view are the likely directions of impactful development over the next few years.

网络生物学是研究生物系统结构、功能和动态的一个强大框架,可为健康和疾病状态之间的平衡提供洞察力。该领域在数据可用性、网络合成、网络分析以及在医学和药物开发中的影响性应用等各个方面都取得了快速进展。我们回顾了网络生物医学的最新重要成果,重点关注最新数据、分析方法、软件资源以及在医学中的应用。我们还讨论了我们认为未来几年有影响力的可能发展方向。
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引用次数: 0
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Current opinion in structural biology
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