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Structural Basis of Main Proteases of Coronavirus Bound to Bofutrelvir 冠状病毒主要蛋白酶与 Bofutrelvir 结合的结构基础。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-06 DOI: 10.1016/j.jmb.2024.168784

Globally, the continuous spread and evolution of SARS-CoV-2, along with its variants, profoundly impact human well-being, health, security, and the growth of socio-economic. In the field of development of drugs against COVID-19, the main protease (Mpro) is a critical target as it plays a core role in the lifecycle of SARS-CoV-2. Bofutrelvir acts as a potent inhibitor of SARS-CoV-2 Mpro, demonstrating high efficacy and broad-spectrum antiviral activity. Compared to therapies that require pharmacokinetic boosters, such as ritonavir, the monotherapy approach of Bofutrelvir reduces the risk of potential drug interactions, making it suitable for a wider patient population. However, further studies on the potency and mechanism of inhibition of Bofutrelvir against the Mpro of COVID-19 and its variants, together with other coronaviruses, are needed to prepare for the possibility of a possible re-emerging threat from an analogous virus in the future. Here, we reveal the effective inhibition of Bofutrelvir against the Mpro of SARS-CoV-2, SARS-CoV, and HCoV-229E through FRET and crystallographic analysis. Furthermore, the inhibitory mechanisms of Bofutrelvir against two SARS-CoV-2 Mpro mutants (G15S and K90R) were also elucidated through FRET and crystallographic studies. Through detailed analysis and comparison of these crystal structures, we identified crucial structural determinants of inhibition and elucidated the binding mode of Bofutrelvir to Mpros from different coronaviruses. These findings are hopeful to accelerate the development of safer and more potent inhibitors against the Mpro of coronavirus, and to provide important references for the prevention and treatment of similar viruses that may emerge in the future.

在全球范围内,SARS-CoV-2 及其变种的持续传播和演变对人类的福祉、健康、安全和社会经济的发展产生了深远的影响。在针对 COVID-19 的药物开发领域,主要蛋白酶(Mpro)是一个关键靶点,因为它在 SARS-CoV-2 的生命周期中发挥着核心作用。Bofutrelvir 是 SARS-CoV-2 Mpro 的强效抑制剂,具有高效、广谱的抗病毒活性。与需要药代动力学促进剂的疗法(如利托那韦)相比,Bofutrelvir 的单药治疗方法降低了潜在药物相互作用的风险,使其适用于更广泛的患者人群。不过,我们还需要进一步研究 Bofutrelvir 对 COVID-19 及其变种以及其他冠状病毒的 Mpro 的抑制效力和机制,以应对未来可能再次出现的类似病毒威胁。在这里,我们通过 FRET 和晶体学分析揭示了 Bofutrelvir 对 SARS-CoV-2、SARS-CoV 和 HCoV-229E 的 Mpro 的有效抑制作用。此外,还通过 FRET 和晶体学研究阐明了 Bofutrelvir 对两种 SARS-CoV-2 Mpro 突变体(G15S 和 K90R)的抑制机制。通过对这些晶体结构的详细分析和比较,我们确定了抑制作用的关键结构决定因素,并阐明了 Bofutrelvir 与不同冠状病毒 Mpro 的结合模式。这些发现有望加速开发更安全、更有效的冠状病毒 Mpro 抑制剂,并为预防和治疗未来可能出现的类似病毒提供重要参考。
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引用次数: 0
Accurate Identification of Periplasmic Urea-binding Proteins by Structure- and Genome Context-assisted Functional Analysis 通过结构和基因组上下文辅助功能分析,准确鉴定外质尿素结合蛋白。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1016/j.jmb.2024.168780

ABC transporters are ancient and ubiquitous nutrient transport systems in bacteria and play a central role in defining lifestyles. Periplasmic solute-binding proteins (SBPs) are components that deliver ligands to their translocation machinery. SBPs have diversified to bind a wide range of ligands with high specificity and affinity. However, accurate assignment of cognate ligands remains a challenging problem in SBPs. Urea metabolism plays an important role in the nitrogen cycle; anthropogenic sources account for more than half of global nitrogen fertilizer. We report identification of urea-binding proteins within a large SBP sequence family that encodes diverse functions. By combining genetic linkage between SBPs, ABC transporter components, enzymes or transcription factors, we accurately identified cognate ligands, as we verified experimentally by biophysical characterization of ligand binding and crystallographic determination of the urea complex of a thermostable urea-binding homolog. Using three-dimensional structure information, these functional assignments were extrapolated to other members in the sequence family lacking genetic linkage information, which revealed that only a fraction bind urea. Using the same combined approaches, we also inferred that other family members bind various short-chain amides, aliphatic amino acids (leucine, isoleucine, valine), γ-aminobutyrate, and as yet unknown ligands. Comparative structural analysis revealed structural adaptations that encode diversification in these SBPs. Systematic assignment of ligands to SBP sequence families is key to understanding bacterial lifestyles, and also provides a rich source of biosensors for clinical and environmental analysis, such as the thermostable urea-binding protein identified here.

ABC 转运体是细菌中古老而无处不在的营养物质转运系统,在确定生命方式方面发挥着核心作用。外质溶质结合蛋白(SBPs)是将配体输送到转运机制的元件。SBPs 种类繁多,能以高特异性和高亲和力结合多种配体。然而,准确分配配体仍然是 SBPs 面临的一个挑战性问题。尿素代谢在氮循环中发挥着重要作用;人为来源占全球氮肥的一半以上。我们报告了在一个编码多种功能的大型 SBP 序列家族中鉴定出的尿素结合蛋白。通过将 SBPs、ABC 转运体成分、酶或转录因子之间的遗传联系结合起来,我们准确地鉴定出了同源配体,并通过配体结合的生物物理表征和恒温尿素结合同源物尿素复合物的晶体学测定进行了实验验证。利用三维结构信息,我们将这些功能分配推断到序列家族中缺乏遗传联系信息的其他成员,结果发现只有一部分能与尿素结合。利用同样的综合方法,我们还推断出其他家族成员结合了各种短链酰胺、脂肪族氨基酸(亮氨酸、异亮氨酸、缬氨酸)、γ -氨基丁酸盐以及尚未知晓的配体。结构比较分析表明,这些 SBPs 的结构适应性编码了多样性。将配体系统地分配到 SBP 序列家族是了解细菌生活方式的关键,同时也为临床和环境分析提供了丰富的生物传感器来源,例如这里发现的恒温尿素结合蛋白。
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引用次数: 0
Pause Patrol: Negative Elongation Factor's Role in Promoter-Proximal Pausing and Beyond. 暂停巡逻队:负延伸因子在启动子-近端暂停及其他过程中的作用
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-04 DOI: 10.1016/j.jmb.2024.168779
Annette J Diao, Bonnie G Su, Seychelle M Vos

RNA polymerase (Pol) II is highly regulated to ensure appropriate gene expression. Early transcription elongation is associated with transient pausing of RNA Pol II in the promoter-proximal region. In multicellular organisms, this pausing is stabilized by the association of transcription elongation factors DRB-sensitivity inducing factor (DSIF) and Negative Elongation Factor (NELF). DSIF is a broadly conserved transcription elongation factor whereas NELF is mostly restricted to the metazoan lineage. Mounting evidence suggests that NELF association with RNA Pol II serves as checkpoint for either release into rapid and productive transcription elongation or premature termination at promoter-proximal pause sites. Here we summarize NELF's roles in promoter-proximal pausing, transcription termination, DNA repair, and signaling based on decades of cell biological, biochemical, and structural work and describe areas for future research.

RNA 聚合酶(Pol)II 受到高度调控,以确保适当的基因表达。早期转录延伸与 RNA Pol II 在启动子近端区域的短暂暂停有关。在多细胞生物中,这种暂停是由转录延伸因子 DRB 敏感性诱导因子(DSIF)和负延伸因子(NELF)联合稳定的。DSIF是一种广泛保守的转录伸长因子,而NELF则主要局限于元虫类。越来越多的证据表明,NELF 与 RNA Pol II 的结合是一种检查点,它可以使转录快速、高产地伸长,也可以使转录在启动子近端暂停位点过早终止。在此,我们根据数十年的细胞生物学、生物化学和结构工作总结了 NELF 在启动子近端暂停、转录终止、DNA 修复和信号转导中的作用,并介绍了未来的研究领域。
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引用次数: 0
RiboVision2: A Web Server for Advanced Visualization of Ribosomal RNAs RiboVision2:核糖体 RNA 高级可视化网络服务器
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jmb.2024.168556

RiboVision2 is a web server designed to visualize phylogenetic, structural, and evolutionary properties of ribosomal RNAs simultaneously at the levels of primary, secondary, and three-dimensional structure and in the context of full ribosomal complexes. RiboVision2 instantly computes and displays a broad variety of data; it has no login requirements, is open-source, free for all users, and available at https://ribovision2.chemistry.gatech.edu.

RiboVision2 是一个网络服务器,用于同时在一级、二级和三维结构层面以及在完整核糖体复合物的背景下可视化核糖体 RNA 的系统发育、结构和进化特性。RiboVision2 可即时计算和显示各种数据;它没有登录要求,是开源的,对所有用户免费,可在 https://ribovision2.chemistry.gatech.edu 上获取。
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引用次数: 0
ModFOLD9: A Web Server for Independent Estimates of 3D Protein Model Quality ModFOLD9:独立评估三维蛋白质模型质量的网络服务器
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jmb.2024.168531

Accurate models of protein tertiary structures are now available from numerous advanced prediction methods, although the accuracy of each method often varies depending on the specific protein target. Additionally, many models may still contain significant local errors. Therefore, reliable, independent model quality estimates are essential both for identifying errors and selecting the very best models for further biological investigations. ModFOLD9 is a leading independent server for detecting the local errors in models produced by any method, and it can accurately discriminate between high-quality models from multiple alternative approaches. ModFOLD9 incorporates several new scores from deep learning-based approaches, leading to greatly improved prediction accuracy compared with earlier versions of the server. ModFOLD9 is continuously independently benchmarked, and it is shown to be highly competitive with other public servers. ModFOLD9 is freely available at https://www.reading.ac.uk/bioinf/ModFOLD/.

目前,许多先进的预测方法都能提供精确的蛋白质三级结构模型,但每种方法的准确性往往因特定蛋白质目标而异。此外,许多模型可能仍然包含明显的局部误差。因此,可靠、独立的模型质量评估对于识别错误和为进一步的生物学研究选择最佳模型至关重要。ModFOLD9 是一个领先的独立服务器,可用于检测任何方法生成的模型中的局部误差,并能准确区分来自多种替代方法的高质量模型。ModFOLD9 采用了基于深度学习方法的多个新分数,与早期版本的服务器相比,预测准确率大大提高。ModFOLD9 不断接受独立基准测试,结果表明它与其他公共服务器相比具有很强的竞争力。ModFOLD9 可在 https://www.reading.ac.uk/bioinf/ModFOLD/ 免费获取。
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引用次数: 0
Alpha&ESMhFolds: A Web Server for Comparing AlphaFold2 and ESMFold Models of the Human Reference Proteome Alpha&ESMhFolds:用于比较人类参考蛋白质组的 AlphaFold2 和 ESMFold 模型的网络服务器。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jmb.2024.168593

We develop a novel database Alpha&ESMhFolds which allows the direct comparison of AlphaFold2 and ESMFold predicted models for 42,942 proteins of the Reference Human Proteome, and when available, their comparison with 2,900 directly associated PDB structures with at least a structure to sequence coverage of 70%. Statistics indicate that good quality models tend to overlap with a TM-score >0.6 as long as some PDB structural information is available. As expected, a direct model superimposition to the PDB structure highlights that AlphaFold2 models are slightly superior to ESMFold ones. However, some 55% of the database is endowed with models overlapping with TM-score <0.6. This highlights the different outputs of the two methods. The database is freely available for usage at https://alpha-esmhfolds.biocomp.unibo.it/.

我们开发了一个新颖的 Alpha&ESMhFolds 数据库,可以直接比较 AlphaFold2 和 ESMFold 预测的 42,942 个参考人类蛋白质组的蛋白质模型,并在有数据的情况下,将其与 2,900 个直接相关的 PDB 结构(结构与序列的覆盖率至少为 70%)进行比较。统计结果表明,只要有一些 PDB 结构信息,高质量的模型往往会与 TM 分数大于 0.6 的模型重叠。不出所料,直接将模型叠加到 PDB 结构上会发现 AlphaFold2 模型略优于 ESMFold 模型。然而,数据库中约有 55% 的模型与 TM-score
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引用次数: 0
IHMCIF: An Extension of the PDBx/mmCIF Data Standard for Integrative Structure Determination Methods IHMCIF:整合结构确定方法的 PDBx/mmCIF 数据标准扩展。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jmb.2024.168546

IHMCIF (github.com/ihmwg/IHMCIF) is a data information framework that supports archiving and disseminating macromolecular structures determined by integrative or hybrid modeling (IHM), and making them Findable, Accessible, Interoperable, and Reusable (FAIR). IHMCIF is an extension of the Protein Data Bank Exchange/macromolecular Crystallographic Information Framework (PDBx/mmCIF) that serves as the framework for the Protein Data Bank (PDB) to archive experimentally determined atomic structures of biological macromolecules and their complexes with one another and small molecule ligands (e.g., enzyme cofactors and drugs). IHMCIF serves as the foundational data standard for the PDB-Dev prototype system, developed for archiving and disseminating integrative structures. It utilizes a flexible data representation to describe integrative structures that span multiple spatiotemporal scales and structural states with definitions for restraints from a variety of experimental methods contributing to integrative structural biology. The IHMCIF extension was created with the benefit of considerable community input and recommendations gathered by the Worldwide Protein Data Bank (wwPDB) Task Force for Integrative or Hybrid Methods (wwpdb.org/task/hybrid). Herein, we describe the development of IHMCIF to support evolving methodologies and ongoing advancements in integrative structural biology. Ultimately, IHMCIF will facilitate the unification of PDB-Dev data and tools with the PDB archive so that integrative structures can be archived and disseminated through PDB.

IHMCIF(github.com/ihmwg/IHMCIF)是一个数据信息框架,支持归档和传播通过整合或混合建模(IHM)确定的大分子结构,并使其具有可查找性、可访问性、可互操作性和可重用性(FAIR)。IHMCIF 是蛋白质数据库交换/大分子晶体学信息框架(PDBx/mmCIF)的扩展,该框架是蛋白质数据库(PDB)的框架,用于归档通过实验确定的生物大分子结构及其相互之间的复合物和小分子配体(如酶辅因子和药物)的原子结构。IHMCIF 是 PDB-Dev 原型系统的基础数据标准,用于归档和传播综合结构。它采用灵活的数据表示方式来描述跨越多个时空尺度和结构状态的整合结构,并定义了各种实验方法对整合结构生物学的限制。全球蛋白质数据库(wwPDB)整合或混合方法工作组(wwpdb.org/task/hybrid)收集了大量的社区意见和建议,IHMCIF扩展就是在这些意见和建议的基础上创建的。在此,我们将介绍 IHMCIF 的发展情况,以支持不断发展的方法和整合结构生物学的持续进步。最终,IHMCIF 将促进 PDB-Dev 数据和工具与 PDB 存档的统一,从而使整合结构可以通过 PDB 存档和传播。
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引用次数: 0
Leaf Senescence Database v5.0: A Comprehensive Repository for Facilitating Plant Senescence Research 叶片衰老数据库 v5.0:促进植物衰老研究的综合资料库。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jmb.2024.168530

Through an extensive literature survey, we have upgraded the Leaf Senescence Database (LSD v5.0; https://ngdc.cncb.ac.cn/lsd/), a curated repository of comprehensive senescence-associated genes (SAGs) and their corresponding mutants. Since its inception in 2010, LSD undergoes frequent updates to encompass the latest advances in leaf senescence research and its current version comprises a high-quality collection of 31,740 SAGs and 1,209 mutants from 148 species, which were manually searched based on robust experimental evidence and further categorized according to their functions in leaf senescence. Furthermore, LSD was greatly enriched with comprehensive annotations for the SAGs through meticulous curation using both manual and computational methods. In addition, it was equipped with user-friendly web interfaces that facilitate text queries, BLAST searches, and convenient download of SAG sequences for localized analysis. Users can effortlessly navigate the database to access a plethora of information, including literature references, mutants, phenotypes, multi-omics data, miRNA interactions, homologs in other plants, and cross-links to various databases. Taken together, the upgraded version of LSD stands as the most comprehensive and informative plant senescence-related database to date, incorporating the largest collection of SAGs and thus bearing great utility for a wide range of studies related to plant senescence.

通过广泛的文献调查,我们升级了叶片衰老数据库(LSD v5.0;https://ngdc.cncb.ac.cn/lsd/),这是一个全面的衰老相关基因(SAGs)及其相应突变体的辑录库。自 2010 年建立以来,LSD 频繁更新,以囊括叶片衰老研究的最新进展,其当前版本包括来自 148 个物种的 31,740 个 SAGs 和 1,209 个突变体的高质量集合,这些集合基于可靠的实验证据进行人工搜索,并根据它们在叶片衰老中的功能进一步分类。此外,LSD 还通过人工和计算方法对 SAGs 进行了细致的整理,大大丰富了 SAGs 的全面注释。此外,该数据库还配备了用户友好型网络界面,方便用户进行文本查询、BLAST 搜索以及下载 SAG 序列进行本地化分析。用户可以轻松浏览数据库,获取大量信息,包括文献参考、突变体、表型、多组学数据、miRNA 相互作用、其他植物中的同源物以及与各种数据库的交叉链接。总之,LSD 的升级版是迄今为止最全面、信息量最大的植物衰老相关数据库,收录了最多的 SAGs,因此在植物衰老相关的广泛研究中大有用武之地。
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引用次数: 0
TPPU_DSF: A Web Application to Calculate Thermodynamic Parameters Using DSF Data TPPU_DSF:利用 DSF 数据计算热力学参数的网络应用程序
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jmb.2024.168519

Here we present TPPU_DSF (https://maciasnmr.net/tppu_dsf/). This is a free and open-source web application that opens, converts, fits, and calculates the thermodynamic parameters of protein unfolding from standard differential scanning fluorimetry (DSF) data in an automated manner. The software has several applications. In the context of screening compound libraries for protein binders, obtaining thermodynamic parameters provides a more robust approach to detecting hits than the changes in the melting temperature (Tm) alone, thereby helping to increase the number of positive hits in screening campaigns. Moreover, changes in ΔGuo indicate protein response to binding at lower compound concentrations than those in the Tm, thereby reducing the costs associated with the amounts of protein and compounds required for the assays. Also, by adding thermodynamic information to the Tm comparison, the software can contribute to the optimization of protein constructs and buffer conditions, a common practice before structural and functional projects.

这里我们介绍 TPPU_DSF (https://maciasnmr.net/tppu_dsf/)。这是一款免费开源的网络应用程序,可自动打开、转换、拟合和计算标准差示扫描荧光光谱仪(DSF)数据中的蛋白质展开热力学参数。该软件有多种应用。在筛选蛋白质结合剂的化合物库中,获得热力学参数提供了一种比单独检测熔化温度(Tm)变化更可靠的方法,从而有助于增加筛选活动中的阳性结果数量。此外,与 Tm 的变化相比,ΔGuo 的变化表明蛋白质在较低化合物浓度下对结合的反应,从而降低了与检测所需的蛋白质和化合物数量相关的成本。此外,通过在 Tm 比较中添加热力学信息,该软件还有助于优化蛋白质结构和缓冲条件,这是结构和功能项目的常见做法。
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引用次数: 0
Computational Resources for Molecular Biology 2024 分子生物学计算资源 2024。
IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-09-01 DOI: 10.1016/j.jmb.2024.168739
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引用次数: 0
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