4RUI

Crystal structure of a cytochrome P450 2A6 in complex with a monoterpene - sabinene.

4RUI の概要

• エントリーDOI: 10.2210/pdb4rui/pdb
• 関連するPDBエントリー: 1Z10 1Z11 2FDU 2FDV 2FDW 2FDY 3EBS 3T3Q 3T3R 4EJJ
• 分子名称: Cytochrome P450 2A6, PROTOPORPHYRIN IX CONTAINING FE, Sabinene, ... (4 entities in total)
• 機能のキーワード: p450, cytochrome p450 2a6, monooxygenase, oxidoreductase, membrane protein, cyp2a6, endoplasmic reticulum, heme, iron, membrane, metal binding, microsome
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Peripheral membrane protein: P11509
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 332546.15

構造登録者

Shah, M.B.,Stout, C.D.,Halpert, J.R. (登録日: 2014-11-19, 公開日: 2015-01-28, 最終更新日: 2024-05-22)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.61 Å)