Flexible structure of cytochrome P450: promiscuity of ligand binding in the CYP3A4 heme pocket.

BACKGROUND: CYP3A4 is the most abundant xenobiotic-metabolizing cytochrome P450 isoform. We examined the structural features of the CYP3A4 molecule with regard to ligand access. MATERIALS AND METHODS: The deleted amino acid sequences of X-ray data sets of CYP3A4s were complemented by molecular modeling techniques. Molecular features of the ligand accessible regions in CYP3A4 were analyzed and their molecular parameters (e.g. dipole moment, solvation free energy, electrostatic potential fields) were determined. RESULTS: Three ligand accessible regions (region 1-3) were present in erythromycin-bound CYP3A4, and these dipole moments indicated the same features as ketoconazole- or metyrapone-bound CYP3A4 molecules. In progesterone-bound CYP3A4, four candidate ligand accessible regions were observed and progesterone could be bound by two selected ligand accessible regions. CONCLUSION: The heme pocket of CYP3A4 is very flexible and is able to interact with various types of substrate.