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Research Themes Drug discovery

Pocket changes

SBKB [doi:10.1038/sbkb.2011.89]
Technical Highlight - July 2012
Short description: Pocketome, an encyclopedia of small-molecule binding sites, helps analyze druggable sites.

Pocketome visualization for the orthosteric site of adenosine receptor A2A, showing regions of steric incompatibility (red transparent spheres) when one ligand is docked into the pocket crystallized with a different ligand.
Figure courtesy of Irina Kufareva.

Small-molecule binding sites have a certain degree of plasticity. An understanding of underlying conformational changes is of interest to scientists ranging from those studying basic cell signaling to drug design. Although a number of databases curate structural information from the PDB for complexes with small molecules, a new resource focuses on details of conformationally variable interaction sites.

Abagyan, Kufareva and colleagues (PSI GPCR Network) developed Pocketome with the aim of compiling three dimensional (3D) structural data for binding sites to understand site flexibility and the effects of fitting various small molecules. For each site, sets of atoms that contact various ligands, defined as pockets, are captured from available experimentally determined structures for that site. Importantly, Pocketome takes into account when sites occur at subunit interfaces or involve a cofactor and metal ions.

The underlying algorithm, siteFinder, automatically collects and analyzes data, outputting Pocketome-binding site ensemble files. Users can analyze data in “pocket” or “site” tabs, both of which include tabulated contacts. The former enables analysis of pocket contacts with its cognate ligand. In addition to a site summary, the latter option allows a cross-compatibility analysis of pockets with other ligands in the ensemble, revealing potential clashes. The results are color coded, facilitating at-a-glance comparisons of contacts. Data also can be visualized in 3D using the ActiveICM browser plug-in.

Pocketome data are sourced from the PDB and the reviewed part of the UniProt Knowledgebase. Sites are added to the encyclopedia when at least two different structures for the protein are available in the PDB, one of which is in complex with a drug-like small molecule. Pocketome is updated automatically as data are added to the PDB and UniProt, leading to expansion of the encyclopedia.

Pocketome is now searchable by protein name, UniProt ID, structure PDB ID or PDB ligand Hetero ID. For future updates, searches by FASTA protein sequence, ligand SMILES string or drug name are planned.

Irene Kaganman

References

  1. I. Kufareva, A.V. Ilatovskiy & R. Abagyan. Pocketome: an encyclopedia of small-molecule binding sites in 4D.
    Nucleic Acids Res. 40, D535-D540 (2012). doi:10.1093/nar/gkr825

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