4RQL

Crystal structure of a human cytochrome P450 2B6 (Y226H/K262R) in complex with a monoterpene - sabinene

Summary for 4RQL

• Entry DOI: 10.2210/pdb4rql/pdb
• Related: 3IBD 3QOA 3QU8 3UA5 4I91
• Descriptor: Cytochrome P450 2B6, PROTOPORPHYRIN IX CONTAINING FE, 5-CYCLOHEXYL-1-PENTYL-BETA-D-MALTOSIDE, ... (6 entities in total)
• Functional Keywords: p450, cytochrome p450 2b6, monooxygenase, membrane protein, cyp2b6, endoplasmic reticulum, heme, iron, metal binding, microsome, oxidoreductase
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P20813
• Total number of polymer chains: 2
• Total formula weight: 113889.02

Authors

Shah, M.B. (deposition date: 2014-11-03, release date: 2015-01-28, Last modification date: 2024-02-28)

Primary citation

Shah, M.B.,Wilderman, P.R.,Liu, J.,Jang, H.H.,Zhang, Q.,Stout, C.D.,Halpert, J.R.
Structural and Biophysical Characterization of Human Cytochromes P450 2B6 and 2A6 Bound to Volatile Hydrocarbons: Analysis and Comparison.
Mol.Pharmacol., 87:649-659, 2015

PubMed Abstract: X-ray crystal structures of complexes of cytochromes CYP2B6 and CYP2A6 with the monoterpene sabinene revealed two distinct binding modes in the active sites. In CYP2B6, sabinene positioned itself with the putative oxidation site located closer to the heme iron. In contrast, sabinene was found in an alternate conformation in the more compact CYP2A6, where the larger hydrophobic side chains resulted in a significantly reduced active-site cavity. Furthermore, results from isothermal titration calorimetry indicated a much more substantial contribution of favorable enthalpy to sabinene binding to CYP2B6 as opposed to CYP2A6, consistent with the previous observations with (+)-α-pinene. Structural analysis of CYP2B6 complexes with sabinene and the structurally similar (3)-carene and comparison with previously solved structures revealed how the movement of the F206 side chain influences the volume of the binding pocket. In addition, retrospective analysis of prior structures revealed that ligands containing -Cl and -NH functional groups adopted a distinct orientation in the CYP2B active site compared with other ligands. This binding mode may reflect the formation of Cl-π or NH-π bonds with aromatic rings in the active site, which serve as important contributors to protein-ligand binding affinity and specificity. Overall, the findings from multiple techniques illustrate how drugs metabolizing CYP2B6 and CYP2A6 handle a common hydrocarbon found in the environment. The study also provides insight into the role of specific functional groups of the ligand that may influence the binding to CYP2B6.

PubMed: 25585967
DOI: 10.1124/mol.114.097014

Experimental method

X-RAY DIFFRACTION (2.105 Å)