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Structural modeling of protein interactions by analogy : application to PSD-95

Korkin, Dmitry and Davis, Fred P. and Alber, Frank and Luong, Tinh and Shen, Min-Yi and Lucic, Vladan and Kennedy, Mary B. and Sali, Andrej (2006) Structural modeling of protein interactions by analogy : application to PSD-95. PLoS Computational Biology, 2 (11). e153. ISSN 1553-734X. PMCID PMC1635541. doi:10.1371/journal.pcbi.0020153.

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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.

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Kennedy, Mary B.0000-0003-1369-0525
Additional Information:Copyright: © 2006 Korkin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: June 8, 2006; Accepted: October 4, 2006; Published: November 10, 2006. A previous version of this article appeared as an Early Online Release on October 5, 2006 (doi:10.1371/journal.pcbi.0020153.eor). We would like to thank the members of the Sali lab for their valuable comments. We also thank Dr. Friedrich Foerster for help in calculating the theoretical SAXS spectra and Dr. Mona Shahgholi for assistance with mass spectrometry and consultation with the limited proteolysis of PSD-95. Author contributions. DK and AS conceived and designed the experiments. DK and TL performed the experiments. DK, FPD, FA, MBK, and AS analyzed the data. DK, FA, TL, MYS, VL, and MBK contributed reagents/materials/analysis tools. DK, FPD, FA, TL, MBK, and AS wrote the paper. Funding. FPD acknowledges a Howard Hughes Medical Institute predoctoral fellowship. TL and MBK acknowledge Materials Research Science and Engineering Centers of the US National Science Foundation for providing partial funds for support of the MALDI–TOF mass spectrometer in the multiuser mass spectrometry laboratory of the Division of Chemistry and Chemical Engineering at California Institute of Technology. We are also grateful for the support of the US National Institutes of Health grant U54 RR022220, US National Science Foundation grant EIA-032645, Human Frontier Science Program, The Sandler Family Supporting Foundation, Hewlett-Packard, NetApps, IBM, and Intel. Competing interests. The authors have declared that no competing interests exist. Accession numbers from the Protein Data Bank ( for the proteins mentioned in this paper are: rat PSD-95 GK (1JXM), rat PSD-95 PDZ3 (1BE9), rat PSD-95 PDZ3 (1BFE), rat PSD-95 SH3 and GK (1JXO), pyruvate formate–lyase protein complex (1CM5). Accession numbers from the European Bioinformatics Institute SMART database ( for proteins mentioned in this paper are: PSD-95 PDZ (SM00228), PSD-95 SH3 (SM00326), and PSD-05 GK (SM00072). Dataset S1. The Best Model of the First Configuration of PSD-95 Core Fragment Dataset S2. The Best Model of the Second Configuration of PSD-95 Core Fragment
Issue or Number:11
PubMed Central ID:PMC1635541
Record Number:CaltechAUTHORS:KORploscb06
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Official Citation:Korkin D, Davis FP, Alber F, Luong T, Shen M-Y, et al. (2006) Structural Modeling of Protein Interactions by Analogy: Application to PSD-95. PLoS Comput Biol 2(11): e153. doi:10.1371/journal.pcbi.0020153
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:6046
Deposited By: Archive Administrator
Deposited On:15 Nov 2006
Last Modified:08 Nov 2021 20:30

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