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The structure of human cytochrome P450 2C9 complexed with flurbiprofen at 2.0 Å resolution

Academic Article
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Overview

authors

  • Wester, M. R.
  • Yano, J. K.
  • Schoch, G. A.
  • Yang, C.
  • Griffin, K. J.
  • Stout, C. David
  • Johnson, Eric

publication date

  • 2004

journal

  • Journal of Biological Chemistry  Journal

abstract

  • The structure of human P450 2C9 complexed with flurbiprofen was determined to 2.0 A by x-ray crystallography. In contrast to other structurally characterized P450 2C enzymes, 2C5, 2C8, and a 2C9 chimera, the native catalytic domain of P450 2C9 differs significantly in the conformation of the helix F to helix G region and exhibits an extra turn at the N terminus of helix A. In addition, a distinct conformation of the helix B to helix C region allows Arg-108 to hydrogen bond with Asp-293 and Asn-289 on helix I and to interact directly with the carboxylate of flurbiprofen. These interactions position the substrate for regioselective oxidation in a relatively large active site cavity and are likely to account for the high catalytic efficiency exhibited by P450 2C9 for the regioselective oxidation of several anionic non-steroidal anti-inflammatory drugs. The structure provides a basis for interpretation of a number of observations regarding the substrate selectivity of P450 2C9 and the observed effects of mutations on catalysis.

subject areas

  • Amino Acid Sequence
  • Aryl Hydrocarbon Hydroxylases
  • Binding Sites
  • Catalytic Domain
  • Cytochrome P-450 CYP2C9
  • Flurbiprofen
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Protein Binding
  • Protein Conformation
  • Substrate Specificity
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.M405427200

PubMed ID

  • 15181000
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Additional Document Info

start page

  • 35630

end page

  • 35637

volume

  • 279

issue

  • 34

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