Korkin Dmitry, Davis Fred P, Alber Frank, Luong Tinh, Shen Min-Yi, Lucic Vladan, Kennedy Mary B, Sali Andrej
Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, United States of America.
PLoS Comput Biol. 2006 Nov 10;2(11):e153. doi: 10.1371/journal.pcbi.0020153. Epub 2006 Oct 4.
We describe comparative patch analysis for modeling the structures of multidomain proteins and protein complexes, and apply it to the PSD-95 protein. Comparative patch analysis is a hybrid of comparative modeling based on a template complex and protein docking, with a greater applicability than comparative modeling and a higher accuracy than docking. It relies on structurally defined interactions of each of the complex components, or their homologs, with any other protein, irrespective of its fold. For each component, its known binding modes with other proteins of any fold are collected and expanded by the known binding modes of its homologs. These modes are then used to restrain conventional molecular docking, resulting in a set of binary domain complexes that are subsequently ranked by geometric complementarity and a statistical potential. The method is evaluated by predicting 20 binary complexes of known structure. It is able to correctly identify the binding mode in 70% of the benchmark complexes compared with 30% for protein docking. We applied comparative patch analysis to model the complex of the third PSD-95, DLG, and ZO-1 (PDZ) domain and the SH3-GK domains in the PSD-95 protein, whose structure is unknown. In the first predicted configuration of the domains, PDZ interacts with SH3, leaving both the GMP-binding site of guanylate kinase (GK) and the C-terminus binding cleft of PDZ accessible, while in the second configuration PDZ interacts with GK, burying both binding sites. We suggest that the two alternate configurations correspond to the different functional forms of PSD-95 and provide a possible structural description for the experimentally observed cooperative folding transitions in PSD-95 and its homologs. More generally, we expect that comparative patch analysis will provide useful spatial restraints for the structural characterization of an increasing number of binary and higher-order protein complexes.
我们描述了用于多结构域蛋白质和蛋白质复合物结构建模的比较补丁分析方法，并将其应用于PSD - 95蛋白。比较补丁分析是基于模板复合物的比较建模与蛋白质对接的混合方法，其适用性比比较建模更广，准确性比对接更高。它依赖于复合物各组分或其同源物与任何其他蛋白质（无论其折叠方式如何）的结构定义相互作用。对于每个组分，收集其与任何折叠方式的其他蛋白质的已知结合模式，并通过其同源物的已知结合模式进行扩展。然后使用这些模式来约束传统的分子对接，从而得到一组二元结构域复合物，随后根据几何互补性和统计势对其进行排序。通过预测20个已知结构的二元复合物对该方法进行评估。与蛋白质对接的30%相比，它能够在70%的基准复合物中正确识别结合模式。我们应用比较补丁分析对PSD - 95蛋白中未知结构的第三个PSD - 95、DLG和ZO - 1（PDZ）结构域与SH3 - GK结构域的复合物进行建模。在结构域的第一个预测构型中，PDZ与SH3相互作用，使得鸟苷酸激酶（GK）的GMP结合位点和PDZ的C末端结合裂隙均保持可及状态，而在第二个构型中，PDZ与GK相互作用，掩埋了两个结合位点。我们认为这两种交替构型对应于PSD - 95的不同功能形式，并为PSD - 95及其同源物中实验观察到的协同折叠转变提供了一种可能的结构描述。更一般地说，我们期望比较补丁分析将为越来越多的二元和高阶蛋白质复合物的结构表征提供有用的空间限制。
