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The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation.

ABSTRACT: Protein-protein and protein-ligand interactions are ubiquitous in a biological cell. Here, we report a comprehensive study of the distribution of protein-ligand interaction sites, namely ligand-binding pockets, around protein-protein interfaces where protein-protein interactions occur. We inspected a representative set of 1,611 representative protein-protein complexes and identified pockets with a potential for binding small molecule ligands. The majority of these pockets are within a 6 ? distance from protein interfaces. Accordingly, in about half of ligand-bound protein-protein complexes, amino acids from both sides of a protein interface are involved in direct contacts with at least one ligand. Statistically, ligands are closer to a protein-protein interface than a random surface patch of the same solvent accessible surface area. Similar results are obtained in an analysis of the ligand distribution around domain-domain interfaces of 1,416 nonredundant, two-domain protein structures. Furthermore, comparable sized pockets as observed in experimental structures are present in artificially generated protein complexes, suggesting that the prominent appearance of pockets around protein interfaces is mainly a structural consequence of protein packing and thus, is an intrinsic geometric feature of protein structure. Nature may take advantage of such a structural feature by selecting and further optimizing for biological function. We propose that packing nearby protein-protein or domain-domain interfaces is a major route to the formation of ligand-binding pockets.

SUBMITTER: Gao M

PROVIDER: S-EPMC3309739 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation.

Gao Mu M Skolnick Jeffrey J

Proceedings of the National Academy of Sciences of the United States of America 20120221 10

Protein-protein and protein-ligand interactions are ubiquitous in a biological cell. Here, we report a comprehensive study of the distribution of protein-ligand interaction sites, namely ligand-binding pockets, around protein-protein interfaces where protein-protein interactions occur. We inspected a representative set of 1,611 representative protein-protein complexes and identified pockets with a potential for binding small molecule ligands. The majority of these pockets are within a 6 Å distan ...[more]

PMID: 22355140

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Project description:Detecting similarities between ligand binding sites in the absence of global homology between target proteins has been recognized as one of the critical components of modern drug discovery. Local binding site alignments can be constructed using sequence order-independent techniques, however, to achieve a high accuracy, many current algorithms for binding site comparison require high-quality experimental protein structures, preferably in the bound conformational state. This, in turn, complicates proteome scale applications, where only various quality structure models are available for the majority of gene products. To improve the state-of-the-art, we developed eMatchSite, a new method for constructing sequence order-independent alignments of ligand binding sites in protein models. Large-scale benchmarking calculations using adenine-binding pockets in crystal structures demonstrate that eMatchSite generates accurate alignments for almost three times more protein pairs than SOIPPA. More importantly, eMatchSite offers a high tolerance to structural distortions in ligand binding regions in protein models. For example, the percentage of correctly aligned pairs of adenine-binding sites in weakly homologous protein models is only 4-9% lower than those aligned using crystal structures. This represents a significant improvement over other algorithms, e.g. the performance of eMatchSite in recognizing similar binding sites is 6% and 13% higher than that of SiteEngine using high- and moderate-quality protein models, respectively. Constructing biologically correct alignments using predicted ligand binding sites in protein models opens up the possibility to investigate drug-protein interaction networks for complete proteomes with prospective systems-level applications in polypharmacology and rational drug repositioning. eMatchSite is freely available to the academic community as a web-server and a stand-alone software distribution at http://www.brylinski.org/ematchsite.

Dataset Information

The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation.

Publications

The distribution of ligand-binding pockets around protein-protein interfaces suggests a general mechanism for pocket formation.

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