Modelling of P450 Active Site Based on Consensus 3d Structures

P450 enzymes constitute a large superfamily of haemthiolate proteins involved in the metabolism of numerous substrates such as drugs, carcinogens and sex hormones. Description of the structure of cytochrome P450 active sites is a key element to design better drugs. However, to date there are less than 150 known structures of P450 proteins. The generation of biologically meaningful 3D patterns or motifs from the simultaneous alignment of several P450 structures is a way of overcoming that lack of data. In order to address this problem, we investigated the simultaneous structural alignments of these proteins. Our new method is based on the comparison of sets of homologue proteins the 3D structures of which are known. Proteins are aligned according to the position of their haem groups. Then, from that multiple alignment, a consensus 3D template is produced providing information concerning atom and chemical group positions as well as cavity location. Experiments on human CYP17 show that these templates contain biologically significant patterns and highlight residues involved in catalytic reactions. Moreover, our 3D templates prove consistent with models of CYP17 active sites generated independently. Therefore, these 3D templates could be exploited for drug design.