Medicinal Chemistry Research Group and National Laboratory for Drug Researchand Development, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary.
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
Nucleic Acids Res. 2023 Jul 5;51(W1):W542-W552. doi: 10.1093/nar/gkad420.
SH2 domains are key mediators of phosphotyrosine-based signalling, and therapeutic targets for diverse, mostly oncological, disease indications. They have a highly conserved structure with a central beta sheet that divides the binding surface of the protein into two main pockets, responsible for phosphotyrosine binding (pY pocket) and substrate specificity (pY + 3 pocket). In recent years, structural databases have proven to be invaluable resources for the drug discovery community, as they contain highly relevant and up-to-date information on important protein classes. Here, we present SH2db, a comprehensive structural database and webserver for SH2 domain structures. To organize these protein structures efficiently, we introduce (i) a generic residue numbering scheme to enhance the comparability of different SH2 domains, (ii) a structure-based multiple sequence alignment of all 120 human wild-type SH2 domain sequences and their PDB and AlphaFold structures. The aligned sequences and structures can be searched, browsed and downloaded from the online interface of SH2db (http://sh2db.ttk.hu), with functions to conveniently prepare multiple structures into a Pymol session, and to export simple charts on the contents of the database. Our hope is that SH2db can assist researchers in their day-to-day work by becoming a one-stop shop for SH2 domain related research.
SH2 结构域是基于磷酸酪氨酸的信号转导的关键介质，也是多种（主要为肿瘤学）疾病适应症的治疗靶点。它们具有高度保守的结构，其中央β片层将蛋白质的结合表面分为两个主要口袋，负责磷酸酪氨酸结合（pY 口袋）和底物特异性（pY+3 口袋）。近年来，结构数据库已被证明是药物发现社区非常宝贵的资源，因为它们包含了重要蛋白质类别的高度相关和最新信息。在这里，我们介绍了 SH2db，这是一个用于 SH2 结构域结构的综合结构数据库和网络服务器。为了有效地组织这些蛋白质结构，我们引入了（i）一种通用的残基编号方案，以增强不同 SH2 结构域的可比性，（ii）对所有 120 个人类野生型 SH2 结构域序列及其 PDB 和 AlphaFold 结构进行基于结构的多重序列比对。对齐的序列和结构可以从 SH2db 的在线界面（http://sh2db.ttk.hu）进行搜索、浏览和下载，该界面具有方便地将多个结构准备到 PyMOL 会话中，并导出有关数据库内容的简单图表的功能。我们希望 SH2db 可以通过成为与 SH2 结构域相关研究的一站式服务，来帮助研究人员开展日常工作。
