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.


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.


CONCLUSIONS
The heme pocket of CYP3A4 is very flexible and is able to interact with various types of substrate.
Faculty of Pharmacy, Chiba Institute of Science, Choshi, Chiba, 288-0025, Japan. kohkura@sag.bekkoame.ne.jp
Kazuto
K
Ohkura
Yuki
Y
Kawaguchi
Yasuko
Y
Watanabe
Yasuhiro
Y
Masubuchi
Yasuo
Y
Shinohara
Hitoshi
H
Hori
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism; D004917:Erythromycin / Q000378:metabolism; D006418:Heme / Q000737:chemistry*; D006801:Humans; D007654:Ketoconazole / Q000378:metabolism; D008024:Ligands; D008797:Metyrapone / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011374:Progesterone / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D055672:Static Electricity; D013379:Substrate Specificity
D008024:Ligands; D006418:Heme; D011374:Progesterone; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D007654:Ketoconazole; D008797:Metyrapone