AHoJ-DB: A PDB-wide Assignment of apo & holo Relationships Based on Individual Protein–Ligand Interactions

IF 4.7 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Molecular Biology Pub Date : 2024-09-01 DOI:10.1016/j.jmb.2024.168545
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Abstract

A single protein structure is rarely sufficient to capture the conformational variability of a protein. Both bound and unbound (holo and apo) forms of a protein are essential for understanding its geometry and making meaningful comparisons. Nevertheless, docking or drug design studies often still consider only single protein structures in their holo form, which are for the most part rigid. With the recent explosion in the field of structural biology, large, curated datasets are urgently needed. Here, we use a previously developed application (AHoJ) to perform a comprehensive search for apo-holo pairs for 468,293 biologically relevant protein–ligand interactions across 27,983 proteins. In each search, the binding pocket is captured and mapped across existing structures within the same UniProt, and the mapped pockets are annotated as apo or holo, based on the presence or absence of ligands. We assemble the results into a database, AHoJ-DB (www.apoholo.cz/db), that captures the variability of proteins with identical sequences, thereby exposing the agents responsible for the observed differences in geometry. We report several metrics for each annotated pocket, and we also include binding pockets that form at the interface of multiple chains. Analysis of the database shows that about 24% of the binding sites occur at the interface of two or more chains and that less than 50% of the total binding sites processed have an apo form in the PDB. These results can be used to train and evaluate predictors, discover potentially druggable proteins, and reveal protein- and ligand-specific relationships that were previously obscured by intermittent or partial data.

Availability: www.apoholo.cz/db

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AHoJ-DB:基于单个蛋白质与配体的相互作用,在整个 PDB 范围内分配 apo 和 holo 关系。
单一的蛋白质结构很少足以捕捉到蛋白质的构象变化。要了解蛋白质的几何结构并进行有意义的比较,蛋白质的结合型和非结合型(整体型和非整体型)都是必不可少的。然而,对接或药物设计研究通常仍然只考虑整体形式的单一蛋白质结构,这种结构大多是刚性的。随着最近结构生物学领域的爆炸式发展,迫切需要大型的、经过整理的数据集。在这里,我们使用以前开发的应用程序(AHoJ)对 27983 个蛋白质中 468293 个与生物学相关的蛋白质-配体相互作用的 apo-holo 对进行了全面搜索。在每次搜索中,我们都会捕捉结合口袋,并将其映射到同一 UniProt 中的现有结构中,然后根据配体的存在或不存在,将映射口袋标注为 apo 或 holo。我们将结果汇总到一个数据库 AHoJ-DB (www.apoholo.cz/db),该数据库捕捉了具有相同序列的蛋白质的变异性,从而揭示了造成所观察到的几何差异的原因。我们报告了每个注释口袋的若干指标,还包括在多链界面形成的结合口袋。对数据库的分析表明,约 24% 的结合位点出现在两条或两条以上链的界面上,而在 PDB 中处理过的总结合位点中,有 apo 形式的不到 50%。这些结果可用于训练和评估预测因子,发现潜在的可药用蛋白质,并揭示蛋白质和配体之间的特异性关系,而这些关系以前因数据断断续续或部分数据而模糊不清。可用性:http://apoholo.cz/db。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal of Molecular Biology
Journal of Molecular Biology 生物-生化与分子生物学
CiteScore
11.30
自引率
1.80%
发文量
412
审稿时长
28 days
期刊介绍: Journal of Molecular Biology (JMB) provides high quality, comprehensive and broad coverage in all areas of molecular biology. The journal publishes original scientific research papers that provide mechanistic and functional insights and report a significant advance to the field. The journal encourages the submission of multidisciplinary studies that use complementary experimental and computational approaches to address challenging biological questions. Research areas include but are not limited to: Biomolecular interactions, signaling networks, systems biology; Cell cycle, cell growth, cell differentiation; Cell death, autophagy; Cell signaling and regulation; Chemical biology; Computational biology, in combination with experimental studies; DNA replication, repair, and recombination; Development, regenerative biology, mechanistic and functional studies of stem cells; Epigenetics, chromatin structure and function; Gene expression; Membrane processes, cell surface proteins and cell-cell interactions; Methodological advances, both experimental and theoretical, including databases; Microbiology, virology, and interactions with the host or environment; Microbiota mechanistic and functional studies; Nuclear organization; Post-translational modifications, proteomics; Processing and function of biologically important macromolecules and complexes; Molecular basis of disease; RNA processing, structure and functions of non-coding RNAs, transcription; Sorting, spatiotemporal organization, trafficking; Structural biology; Synthetic biology; Translation, protein folding, chaperones, protein degradation and quality control.
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