title: Architectural repertoire of ligand-binding pockets on protein surfaces.
abstract: Knowledge of the three-dimensional structure of ligand binding sites in proteins provides valuable information for computer-assisted drug design. We present a method for the automated extraction and classification of ligand binding site topologies, in which protein surface cavities are represented as branched frameworks. The procedure employs a growing neural gas approach for pocket topology assignment and pocket framework generation. We assessed the structural diversity of 623 known ligand binding site topologies based on framework cluster analysis. At a resolution of 5 A only 23 structurally distinct topology groups were formed; this suggests an overall limited structural diversity of ligand-accommodating protein cavities. Higher resolution allowed for identification of protein-family specific pocket features. Pocket frameworks highlight potentially preferred modes of ligand-receptor interactions and will help facilitate the identification of druggable subpockets suitable for ligand affinity and selectivity optimization.
authors.affiliation: Johann Wolfgang Goethe-University, Institute of Organic Chemistry and Chemical Biology, Siesmayerstr. 70, 60323 Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Weisel
authors.forename: Jan M
authors.initials: JM
authors.lastname: Kriegl
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D001665:Binding Sites; D030562:Databases, Protein; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D016571:Neural Networks, Computer; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D012441:Saccharomyces cerevisiae / Q000737:chemistry; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry
chemical_list: D018841:HSP90 Heat-Shock Proteins; D008024:Ligands; D011506:Proteins; D029701:Saccharomyces cerevisiae Proteins