CYP2C9 catalytic domain showing positions of *2 and *3 polymorphisms

X-ray crystal structure of human CYP2C9 (PDB id=1R9O (http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1R9O)) showing the positions of the amino acids altered by the CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu) polymorphisms relative to the six substrate recognition sites (SRSs). The Arg144 and Ile359 sidechains are shown as space-filling spheres colored according to element type (C=white, N=blue, O=red). The heme group is also colored according to element (Fe=orange). The key sidechains in each of the six SRSs are colored according to SRS: SRS1 (red; Val113, Phe114); SRS2 (orange; Ile205, Leu208); SRS3 (yellow; Val237, Met240); SRS4 (green; Gly296, Ala297); SRS5 (blue; Leu366); SRS6 (magenta; Phe 476). The CYP2C9*2 (Arg144Cys) allele is thought to give rise to a form of CYP2C9 with reduced affinity for its cofactor, P450 reductase. The P450 activity of the enzyme resulting from the CYP2C9*3 (Ile359Leu) allele has a lower Vmax and lower substrate Km than wild type CYP2C9, presumably due to indirect conformational effects of the sidechain substitution on the enzyme active site. Figure and animation were created using PyMol.