Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone

  • Williams P
  • Cosme J
  • Matak Vinković D
 et al. 
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Abstract

Cytochromes P450 (P450s) metabolize a wide range of endogenous compounds and xenobiotics, such as pollutants, environmental compounds, and drug molecules. The microsomal, membrane-associated, P450 isoforms CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1, and CYP1A2 are responsible for the oxidative metabolism of more than 90% of marketed drugs. Cytochrome P450 3A4 (CYP3A4) metabolizes more drug molecules than all other isoforms combined. Here we report three crystal structures of CYP3A4: unliganded, bound to the inhibitor metyrapone, and bound to the substrate progesterone. The structures revealed a surprisingly small active site, with little conformational change associated with the binding of either compound. An unexpected peripheral binding site is identified, located above a phenylalanine cluster, which may be involved in the initial recognition of substrates or allosteric effectors.

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Authors

  • Pamela A. Williams

  • Jose Cosme

  • Dijana Matak Vinković

  • Alison Ward

  • Hayley C. Angove

  • Philip J. Day

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