4gqs

Publication Abstract from PubMed

In order to identify structural features underlying the distinct substrate and inhibitor profiles of P450 2C19 relative to the closely related human enzymes, P450s 2C8 and 2C9, the atomic structure (PDB#4GQS) of cytochrome P450 2C19 complexed with the inhibitor (2-methyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-dimethylphenyl)methanone (PDB chemical component: 0XV) was determined to 2.87 A resolution by x-ray crystallography. The conformation of the peptide backbone of P450 2C19 is most similar to that of P450 2C8, but the substrate binding cavity of P450 2C8 is much larger than that of P450 2C19 due to differences in the amino acid residues that form the substrate binding cavities of the two enzymes. In contrast, the substrate binding cavity of P450 2C19 is much more similar in size to that of the structure of P450 2C9 flurbiprofen complex than to that of a modified P450 2C9 or that of P450 2C8. The cavities of P450 2C19 0XV complex and the P450 2C9 flurbiprofen complex differ, however, because the helix B-C loops of the two enzymes are dissimilar. These conformation differences reflect effects of adjacent structural elements that interact with the B-C loops and that differ between the two enzymes. The availability of a structure for 2C19 will facilitate computational approaches for predictions of substrate and inhibitor binding to this enzyme.

Structural characterization of human cytochrome P450 2C19: active site differences between P450's 2C8, 2C9 and 2C19.,Reynald RL, Sansen S, Stout CD, Johnson EF J Biol Chem. 2012 Nov 1. PMID:23118231^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.