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Molecular basis of conjugation-mediated DNA transfer by gram-negative bacteria 革兰氏阴性菌偶联介导DNA转移的分子基础。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.sbi.2024.102978
Gabriel Waksman
Bacterial conjugation is the unidirectional transfer of DNA (often plasmids, but also other mobile genetic elements, or even entire genomes), from a donor cell to a recipient cell. In Gram-negative bacteria, it requires the formation of three complexes in the donor cell: i-a large, double-membrane-embedded transport machinery called the Type IV Secretion System (T4SS), ii-a long extracellular tube, the conjugative pilus, and iii-a DNA-processing machinery termed the relaxosome. While knowledge has expanded regarding molecular events in the donor cell, very little is known about the machinery involved in DNA transfer into the recipient cell. Here, focusing on systems principally involved in DNA transfer, we provide an update on progress made on various mechanistic aspects of conjugation.
细菌偶联是DNA(通常是质粒,但也有其他可移动的遗传元素,甚至是整个基因组)从供体细胞向受体细胞的单向转移。在革兰氏阴性菌中,它需要在供体细胞中形成三种复合物:i-一个大的,双膜嵌入的运输机制,称为IV型分泌系统(T4SS), ii-一个长细胞外管,接合菌毛,和iii-一个称为松弛体的dna加工机制。虽然对供体细胞中的分子事件的了解已经扩大,但对DNA转移到受体细胞的机制知之甚少。在这里,专注于系统主要涉及DNA转移,我们提供了在缀合的各种机制方面取得的进展的更新。
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引用次数: 0
Protein binding and folding through an evolutionary lens 从进化的角度看蛋白质的结合和折叠。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2025-02-01 DOI: 10.1016/j.sbi.2024.102980
Per Jemth
Protein–protein associations are often mediated by an intrinsically disordered protein region interacting with a folded domain in a coupled binding and folding reaction. Classic physical organic chemistry approaches together with structural biology have shed light on mechanistic aspects of such reactions. Further insight into general principles may be obtained by interpreting the results through an evolutionary lens. This review attempts to provide an overview on how the analysis of binding and folding reactions can benefit from an evolutionary approach, and is aimed at protein scientists without a background in evolution. Evolution constantly reshapes existing proteins by sampling more or less fit variants. Most new variants are weeded out as generations and new species come and go over hundreds to hundreds of millions of years. The huge ongoing genome sequencing efforts have provided us with a snapshot of existing adapted fit-for-purpose protein homologs in thousands of different organisms. Comparison of present-day orthologs and paralogs highlights general principles of the evolution of coupled binding and folding reactions and demonstrate a great potential for evolution to operate on disordered regions and modulate affinity and specificity of the interactions.
蛋白质之间的结合通常是由一个内在无序的蛋白质区域在一个耦合的结合和折叠反应中与一个折叠结构域相互作用介导的。经典的物理有机化学方法与结构生物学一起揭示了这种反应的机制方面。通过从进化的角度来解释这些结果,可以获得对一般原理的进一步了解。这篇综述试图概述结合和折叠反应的分析如何从进化方法中受益,并针对没有进化背景的蛋白质科学家。进化不断地通过取样或多或少适合的变异来重塑现有的蛋白质。大多数新的变异会随着一代又一代的进化而被淘汰,新物种的出现和消失需要数亿年的时间。正在进行的巨大的基因组测序工作为我们提供了数千种不同生物中现有的适应适合目的的蛋白质同源物的快照。目前的同源物和相似物的比较突出了耦合结合和折叠反应进化的一般原理,并展示了在无序区域上操作和调节相互作用的亲和力和特异性的巨大潜力。
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引用次数: 0
Protein-nucleic acid complexes: Docking and binding affinity 蛋白质-核酸复合物:对接和结合亲和力
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-30 DOI: 10.1016/j.sbi.2024.102955
M. Michael Gromiha, K. Harini
Protein-nucleic interactions play essential roles in several biological processes, such as gene regulation, replication, transcription, repair and packaging. The knowledge of three-dimensional structures of protein-nucleic acid complexes and their binding affinities helps to understand these functions. In this review, we focus on two major aspects namely, (i) deciphering the three-dimensional structures of protein-nucleic acid complexes and (ii) predicting their binding affinities. The first part is devoted to the state-of-the-art methods for predicting the native structures and their performances including recent CASP targets. The second part is focused on different aspects of investigating the binding affinity of protein-nucleic acid complexes: (i) databases for thermodynamic parameters to understand the binding affinity, (ii) important features determining protein-nucleic acid binding affinity, (iii) predicting the binding affinity of protein-nucleic acid complexes using sequence and structure-based parameters and (iv) change in binding affinity upon mutation. It includes the latest developments in protein-nucleic acid docking algorithms and binding affinity predictions along with a list of computational resources for understanding protein-DNA and protein-RNA interactions.
蛋白-核相互作用在基因调控、复制、转录、修复和包装等多种生物过程中发挥着重要作用。了解蛋白质-核酸复合物的三维结构及其结合亲和力有助于理解这些功能。在这篇综述中,我们集中在两个主要方面,即(i)破译蛋白质-核酸复合物的三维结构和(ii)预测它们的结合亲和力。第一部分致力于预测原生结构及其性能的最先进方法,包括最近的CASP目标。第二部分侧重于研究蛋白质-核酸复合物结合亲和力的不同方面:(i)了解结合亲和力的热力学参数数据库,(ii)确定蛋白质-核酸结合亲和力的重要特征,(iii)使用基于序列和结构的参数预测蛋白质-核酸复合物的结合亲和力,以及(iv)结合亲和力随突变的变化。它包括蛋白质-核酸对接算法和结合亲和力预测的最新发展,以及用于理解蛋白质- dna和蛋白质- rna相互作用的计算资源列表。
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引用次数: 0
Protein data bank: From two epidemics to the global pandemic to mRNA vaccines and Paxlovid 蛋白质数据库:从两次流行病到全球大流行,再到 mRNA 疫苗和 Paxlovid
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-24 DOI: 10.1016/j.sbi.2024.102954
Stephen K. Burley
Structural biologists and the open-access Protein Data Bank (PDB) played decisive roles in combating the COVID-19 pandemic. Global biostructure data were turned into global knowledge, allowing scientists and engineers to understand the inner workings of coronaviruses and develop effective countermeasures. Two mRNA vaccines, initially designed with guidance from PDB structures of the SARS-CoV-1 and MERS-CoV spike proteins, prevented infections entirely or reduced the likelihood of morbidity and mortality for more than five billion individual recipients worldwide. Structure-guided drug discovery by Pfizer, Inc (facilitated by PDB structures), initiated in the 2000s in response to SARS-CoV-1 and resumed in 2020, yielded nirmatrelvir (the active ingredient of Paxlovid) -- a potent, orally-bioavailable inhibitor of the SARS-CoV-2 main protease. You've got to love the Protein Data Bank!
结构生物学家和开放式蛋白质数据库(PDB)在抗击 COVID-19 大流行中发挥了决定性作用。全球生物结构数据被转化为全球知识,使科学家和工程师能够了解冠状病毒的内部运作,并开发出有效的应对措施。最初根据 SARS-CoV-1 和 MERS-CoV 尖峰蛋白的 PDB 结构指导设计的两种 mRNA 疫苗,为全球 50 多亿受试者完全防止了感染或降低了发病和死亡的可能性。辉瑞公司(Pfizer, Inc)于 2000 年代针对 SARS-CoV-1 启动了以结构为导向的药物研发(PDB 结构为研发提供了便利),并于 2020 年重新启动,研发出了 nirmatrelvir(Paxlovid 的活性成分)--一种强效的 SARS-CoV-2 主要蛋白酶口服生物抑制剂。你一定会爱上蛋白质数据库!
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引用次数: 0
Characterizing heterogeneity in amyloid formation processes 淀粉样蛋白形成过程中的异质性特征。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-19 DOI: 10.1016/j.sbi.2024.102951
Hoi Sung Chung
Protein aggregation is a complex process, consisting of a large number of pathways connecting monomers and mature amyloid fibrils. Recent advances in structure determination techniques, such as solid-state NMR and cryoEM, have allowed the determination of atomic resolution structures of fibril polymorphs, but most of the intermediate stages of the process including oligomer formation remain unknown. Proper characterization of the heterogeneity of the process is critical not only for physical and chemical understanding of the aggregation process but also for elucidation of the disease mechanisms and identification of therapeutic targets. This article reviews recent developments in the characterization of heterogeneity in amyloid formation processes.
蛋白质聚集是一个复杂的过程,由连接单体和成熟淀粉样纤维的大量途径组成。固态核磁共振和低温电子显微镜等结构测定技术的最新进展使人们能够测定纤维多态的原子分辨率结构,但这一过程的大部分中间阶段(包括低聚物的形成)仍然未知。正确表征这一过程的异质性不仅对理解聚集过程的物理和化学性质至关重要,而且对阐明疾病机制和确定治疗靶点也至关重要。本文回顾了表征淀粉样蛋白形成过程异质性的最新进展。
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引用次数: 0
Biochemistry and genetics are coming together to improve our understanding of genotype to phenotype relationships 生物化学和遗传学正在结合在一起,以提高我们对基因型与表型关系的理解。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1016/j.sbi.2024.102952
Judith Notbohm , Tina Perica
Since genome sequencing became accessible, determining how specific differences in genotypes lead to complex phenotypes such as disease has become one of the key goals in biomedicine. Predicting effects of sequence variants on cellular or organismal phenotype faces several challenges. First, variants simultaneously affect multiple protein properties and predicting their combined effect is complex. Second, effects of changes in a single protein propagate through the cellular network, which we only partially understand. In this review, we emphasize the importance of both biochemistry and genetics in addressing these challenges. Moreover, we highlight work that blurs the distinction between biochemistry and genetics fields to provide new insights into the genotype-to-phenotype relationships.
自基因组测序开始普及以来,确定基因型的具体差异如何导致疾病等复杂表型已成为生物医学的关键目标之一。预测序列变异对细胞或生物体表型的影响面临着几个挑战。首先,变异同时影响多种蛋白质特性,预测它们的综合效应非常复杂。其次,单个蛋白质变化的影响会通过细胞网络传播,而我们对细胞网络只有部分了解。在这篇综述中,我们强调了生物化学和遗传学在应对这些挑战中的重要性。此外,我们还着重介绍了一些模糊生物化学和遗传学领域界限的工作,这些工作为我们提供了基因型与表型关系的新见解。
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引用次数: 0
Deep learning for intrinsically disordered proteins: From improved predictions to deciphering conformational ensembles 内在无序蛋白质的深度学习:从改进预测到解密构象组合。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1016/j.sbi.2024.102950
Gábor Erdős, Zsuzsanna Dosztányi
Intrinsically disordered proteins (IDPs) lack a stable three-dimensional structure under physiological conditions, challenging traditional structure-based prediction methods. This review explores how modern deep learning approaches, which have revolutionized structure prediction for globular proteins, have impacted protein disorder predictions. We highlight the role of community-driven efforts in curating data and assessing state-of-the-art, which have been crucial in advancing the field. We also review state-of-the-art methods utilizing deep learning techniques, highlighting innovative approaches. We also address advancements in characterizing protein conformational ensembles directly from sequence data using novel machine learning methods.
本质无序蛋白(IDPs)在生理条件下缺乏稳定的三维结构,这对传统的基于结构的预测方法提出了挑战。本综述探讨了现代深度学习方法对蛋白质无序预测的影响,这些方法已经彻底改变了球蛋白的结构预测。我们强调了由社区推动的数据整理和最新技术评估工作的作用,这对推动该领域的发展至关重要。我们还回顾了利用深度学习技术的最新方法,重点介绍了创新方法。我们还探讨了利用新型机器学习方法直接从序列数据中鉴定蛋白质构象组合的进展。
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引用次数: 0
Short circuit: Transcription factor addiction as a growing vulnerability in cancer 短路:转录因子成瘾是癌症中一个日益严重的弱点。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-12 DOI: 10.1016/j.sbi.2024.102948
Molly Davies, Maeve Boyce, Eric Conway
Core regulatory circuitry refers to the network of lineage-specific transcription factors regulating expression of both their own coding genes, and that of other transcription factors. Such autoregulatory feedback loops coordinate the transcriptome and epigenome during development and cell fate decisions. This circuitry is hijacked during oncogenesis resulting in cancer cell fate being maintained by lineage-specific transcription factors. Major advances in functional genomics and chemical biology are paving the way for a new generation of cancer therapeutics aimed at disrupting this circuitry through both direct and indirect means. Here we review these critical advances in mechanistic understanding of transcription factor addiction in cancer and how the advent of proteolysis targeting chimeras and CRISPR screen assays are leading the way for a new paradigm in targeted cancer treatments.
核心调控回路指的是由各系特异性转录因子组成的网络,它们既调控自身编码基因的表达,也调控其他转录因子的表达。这种自调节反馈回路在发育和细胞命运决定过程中协调转录组和表观基因组。这种回路在肿瘤发生过程中被劫持,导致癌细胞的命运由特异性转录因子维持。功能基因组学和化学生物学的重大进展为新一代癌症疗法铺平了道路,这些疗法旨在通过直接和间接手段破坏这种回路。在此,我们将回顾在癌症转录因子成瘾的机理认识方面取得的这些重要进展,以及蛋白水解靶向嵌合体和 CRISPR 筛选测定的出现如何引领癌症靶向治疗的新范例。
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引用次数: 0
Conformational penalties: New insights into nucleic acid recognition 构象惩罚:核酸识别的新见解。
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-09 DOI: 10.1016/j.sbi.2024.102949
Ainan Geng , Rohit Roy , Hashim M. Al-Hashimi
The energy cost accompanying changes in the structures of nucleic acids when they bind partner molecules is a significant but underappreciated thermodynamic contribution to binding affinity and specificity. This review highlights recent advances in measuring conformational penalties and determining their contribution to the recognition, folding, and regulatory activities of nucleic acids. Notable progress includes methods for measuring and structurally characterizing lowly populated conformational states, obtaining ensemble information in high throughput, for large macromolecular assemblies, and in complex cellular environments. Additionally, quantitative and predictive thermodynamic models have been developed that relate conformational penalties to nucleic acid-protein association and cellular activity. These studies underscore the crucial role of conformational penalties in nucleic acid recognition.
核酸与伙伴分子结合时,伴随其结构变化而产生的能量成本是对结合亲和力和特异性的重要热力学贡献,但这一贡献却未得到充分重视。本综述重点介绍了在测量构象惩罚并确定其对核酸识别、折叠和调控活动的贡献方面的最新进展。值得注意的进展包括测量和从结构上描述低密度构象状态的方法,以及在高通量、大分子组装和复杂细胞环境中获取集合信息的方法。此外,还开发了定量和预测性热力学模型,将构象惩罚与核酸-蛋白质关联和细胞活性联系起来。这些研究强调了构象惩罚在核酸识别中的关键作用。
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引用次数: 0
The mechano-chemistry of a viral genome packaging motor 病毒基因组包装马达的机械化学原理
IF 6.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-11-04 DOI: 10.1016/j.sbi.2024.102945
Joshua Pajak , Nikolai S. Prokhorov , Paul J. Jardine , Marc C. Morais
Double-stranded DNA viruses actively package their genomes into pre-assembled protein capsids using energy derived from virus-encoded ASCE ATPase ring motors. Single molecule experiments in the aughts and early 2010s demonstrated that these motors are some of the most powerful molecular motors in nature, and that the activities of individual subunits around the ATPase ring motor are highly coordinated to ensure efficient genome encapsidation. While these studies provided a comprehensive kinetic scheme describing the events that occur during packaging, the physical basis of force generation and subunit coordination remained elusive. This article reviews recent structural and computational results that have begun to illuminate the molecular basis of force generation and DNA translocation in these powerful molecular motors.
双链DNA病毒利用病毒编码的ASCE ATPase环马达产生的能量,积极地将其基因组包装到预先组装好的蛋白囊壳中。二十世纪八十年代和二十一世纪初的单分子实验证明,这些马达是自然界中一些最强大的分子马达,ATPase 环马达周围各个亚基的活动高度协调,以确保高效的基因组封装。虽然这些研究提供了一个全面的动力学方案来描述包装过程中发生的事件,但力的产生和亚基协调的物理基础仍然难以捉摸。本文回顾了最近的结构和计算成果,这些成果已开始阐明这些强大分子马达产生作用力和 DNA 转位的分子基础。
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引用次数: 0
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Current opinion in structural biology
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