3QOA

Crystal structure of a human cytochrome P450 2B6 (Y226H/K262R) in complex with the inhibitor 4-Benzylpyridine.

Summary for 3QOA

• Entry DOI: 10.2210/pdb3qoa/pdb
• Related: 3IBD 3QU8
• Descriptor: Cytochrome P450 2B6, PROTOPORPHYRIN IX CONTAINING FE, 5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE, ... (5 entities in total)
• Functional Keywords: p450, cytochrome p450 2b6, monooxygenase, membrane protein, cyp2b6, endoplasmic reticulum, heme, iron, membrane, metal binding, mircosome, phosphoprotein, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P20813
• Total number of polymer chains: 1
• Total formula weight: 56420.86

Authors

Shah, M.B.,Pascual, J.,Stout, C.D.,Halpert, J.R. (deposition date: 2011-02-09, release date: 2011-09-14, Last modification date: 2023-09-13)

Primary citation

Shah, M.B.,Pascual, J.,Zhang, Q.,Stout, C.D.,Halpert, J.R.
Structures of Cytochrome P450 2B6 Bound to 4-Benzylpyridine and 4-(4-Nitrobenzyl)pyridine: Insight into Inhibitor Binding and Rearrangement of Active Site Side Chains.
Mol.Pharmacol., 80:1047-1055, 2011

PubMed Abstract: The biochemical, biophysical, and structural analysis of the cytochrome P450 2B subfamily of enzymes has provided a wealth of information regarding conformational plasticity and substrate recognition. The recent X-ray crystal structure of the drug-metabolizing P450 2B6 in complex with 4-(4-chlorophenyl)imidazole (4-CPI) yielded the first atomic view of this human enzyme. However, knowledge of the structural basis of P450 2B6 specificity and inhibition has remained limited. In this study, structures of P450 2B6 were determined in complex with the potent inhibitors 4-benzylpyridine (4-BP) and 4-(4-nitrobenzyl)pyridine (4-NBP). Comparison of the present structures with the previous P450 2B6-4-CPI complex showed that reorientation of side chains of the active site residue Phe206 on the F-helix and Phe297 on the I-helix was necessary to accommodate the inhibitors. However, P450 2B6 does not require any major side chain rearrangement to bind 4-NBP compared with 4-BP, and the enzyme provides no hydrogen-bonding partners for the polar nitro group of 4-NBP within the hydrophobic active site. In addition, on the basis of these new structures, substitution of residue 172 with histidine as observed in the single nucleotide polymorphism Q172H and in P450 2B4 may contribute to a hydrogen bonding network connecting the E- and I-helices, thereby stabilizing active site residues on the I-helix. These results provide insight into the role of active site side chains upon inhibitor binding and indicate that the recognition of the benzylpyridines in the closed conformation structure of P450 2B6 is based solely on hydrophobicity, size, and shape.

PubMed: 21875942
DOI: 10.1124/mol.111.074427

Experimental method

X-RAY DIFFRACTION (2.1 Å)