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

Science. 2004 Jul 30;305(5684):683-6. doi: 10.1126/science.1099736. Epub 2004 Jul 15.

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.

MeSH terms

  • Binding Sites
  • Crystallization
  • Crystallography, X-Ray
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / chemistry*
  • Cytochrome P-450 Enzyme System / metabolism*
  • Heme / chemistry
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Metyrapone / metabolism*
  • Models, Molecular
  • Phenylalanine / chemistry
  • Phenylalanine / metabolism
  • Progesterone / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Water / metabolism

Substances

  • Ligands
  • Water
  • Heme
  • Phenylalanine
  • Progesterone
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Metyrapone

Associated data

  • PDB/1W0E
  • PDB/1W0F
  • PDB/1W0G