SUPERSITES WITHIN SUPERFOLDS - BINDING-SITE SIMILARITY IN THE ABSENCEOF HOMOLOGY

A method is presented to assess the significance of binding site simil arities within superimposed protein three-dimensional (3D) structures and applied toll similar structures in the Protein Data Bank. For simi larities between 3D structures lacking significant sequence similarity , the important distinction was made between remote homology (an ancie nt common ancestor) and analogy (likely convergence to a folding motif ) according to the structural classification of proteins (SCOP) databa se. Supersites, were defined as structural locations on groups of anal ogous proteins (i.e. superfolds) showing a statistically significant t endency to bind substrates despite little evidence of a common ancesto r for the proteins considered. We identify three potentially new super folds containing supersites: ferredoxin-like folds, four-helical bundl es and double-stranded beta helices. In addition, the method quantifie s binding site similarities within homologous proteins and previously identified supersites such as that found in the beta/alpha (TIM) barre ls. For the nine superfolds, the accuracy of predictions of binding si te locations is assessed. Implications for protein evolution, and the prediction of protein function either through fold recognition or tert iary structure comparison, are discussed. (C) 1998 Academic Press.