A 3D model of human P450c21: study of the putative effects of steroid 21-hydroxylase gene mutations

In order to better understand the disease-causing role of missense mutation s found in the CYP21 gene from patients affected with congenital adrenal hy perplasia (CAH) due to steroid 21-hydroxylase deficiency, we built two thre e-dimensional (3D) models of human P450c21 using all known 3D structures of P450s. For each residue affected by a missense mutation, its location in t he 3D structure and the putative changes in terms of biochemical properties brought about by the mutation were analyzed. Most of the severe alleles we re found to affect residues located in functionally important regions of th e molecule such as substrate recognition sites (SRS) or the heme region, wh ereas moderate mutations were mostly found in less crucial regions of the m olecule. Thus, there is a good correlation between the 3D structure study a nd clinical data and mutagenesis experiments previously reported. In one ca se, however, the observed clinical severity of the mutation (E380D) did not match its expected severity deduced from the model, pointing to a potentia l functionally important region of the molecule. Our 3D human models provid e a basic model for further studies of mutations responsible for 21-hydroxy lase, and for identification of important residues involved in the specific activity of the enzyme.