Structural Characterization of Human Cytochrome P450 2C19

ACTIVE SITE DIFFERENCES BETWEEN P450s 2C8, 2C9, AND 2C19*,

  1. Eric F. Johnson,2
  1. From the Departments of Molecular and Experimental Medicine and
  2. §Molecular Biology, The Scripps Research Institute, La Jolla, California 92037
  1. 1 To whom correspondence may be addressed: Dept. of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., MB8, La Jolla, CA 92037. Tel.: 858-784-8738; Fax: 858-784-2857; E-mail: dave{at}scripps.edu.
  2. 2 To whom correspondence may be addressed: Dept. of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Rd., MEM-255, La Jolla, CA 92037. Tel.: 858-784-7918; Fax: 858-784-7978: E-mail: johnson{at}scripps.edu.

Background: Knowledge of the structural features of P450 2C19 that underlie its distinct roles in human drug metabolism is lacking.

Results: The structure of P450 2C19 was determined by x-ray crystallography.

Conclusion: The structure of the enzyme exhibits features that distinguish it from closely related P450s 2C8 and 2C9.

Significance: Structural characterization of P450 2C19 contributes to a better understanding of its role in drug clearance.

Abstract

To identify the 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 (Protein Data Bank code 4GQS) of cytochrome P450 2C19 complexed with the inhibitor (2-methyl-1-benzofuran-3-yl)-(4-hydroxy-3,5-dimethylphenyl)methanone (Protein Data Bank chemical component 0XV) was determined to 2.87 Å 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 the P450 2C9 flurbiprofen complex than to that of a modified P450 2C9 or that of P450 2C8. The cavities of the 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 conformational differences reflect the 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.

Footnotes

  • * This work was supported, in whole or in part, by National Institutes of Health Grant R01GM031001 from NIGMS (to E. F. J.).

  • This article was selected as a Paper of the Week.

  • The atomic coordinates and structure factors (code 4GQS) have been deposited in the Protein Data Bank (http://wwpdb.org/).

  • Received October 2, 2012.
  • Revision received November 1, 2012.

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