Generation of 3D templates of active sites of proteins with rigid prosthetic groups

Abstract

With the increasing availability of protein structures, the generation of biologically meaningful 3D patterns from their simultaneous alignment is an exciting prospect: active sites could be better understood, protein functions and structures could be predicted more accurately. Although patterns can be generated at the fold and topological levels, no system produces high resolution 3D patterns including atom and cavity positions. Here, we present a new approach allowing the generation of 3D patterns from alignment of proteins with rigid prosthetic groups. Using 237 proteins representing these proteins, our method was validated by comparing 3D templates generated from homologues with structures of the proteins they model. Atom positions were predicted reliably: 93% of them had an accuracy below 1.00 Å. Similar results were obtained regarding chemical group and cavity positions. Finally, a 3D template was generated for the active site of human cytochrome P450 CYP17. Its analysis showed it is biologically meaningful: our method detected the main patterns and motifs of the P450 superfamily. The 3D template also suggested the locations of a cavity and of a hydrogen bond between CYP17 and its substrates. Comparisons with independently generated 3D models comforted these hypotheses.