5VEU

Human Cytochrome P450 3A5 (CYP3A5)

5VEU の概要

• エントリーDOI: 10.2210/pdb5veu/pdb
• 関連するBIRD辞書のPRD_ID: PRD_001001
• 分子名称: Cytochrome P450 3A5, PROTOPORPHYRIN IX CONTAINING FE, RITONAVIR (3 entities in total)
• 機能のキーワード: inhibitor, complex, cytochrome p450, ritonavir, cyp3a5, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 667911.71

構造登録者

Hsu, M.-H.,Johnson, E.F. (登録日: 2017-04-05, 公開日: 2017-11-15, 最終更新日: 2023-10-04)

主引用文献

Hsu, M.H.,Savas, U.,Johnson, E.F.
The X-Ray Crystal Structure of the Human Mono-Oxygenase Cytochrome P450 3A5-Ritonavir Complex Reveals Active Site Differences between P450s 3A4 and 3A5.
Mol. Pharmacol., 93:14-24, 2018

PubMed Abstract: The contributions of cytochrome P450 3A5 to the metabolic clearance of marketed drugs is unclear, but its probable role is to augment the metabolism of several drugs that are largely cleared by P450 3A4. Selective metabolism by 3A4 is often a concern in drug development owing to potential drug-drug interactions and the variability of 3A4 and 3A5 expression. The contribution of P450 3A5 to these clearance pathways varies between individuals owing to genetic differences and similarities and differences in the metabolic properties of 3A5 compared with 3A4. To better understand the structural differences between P450s 3A4 and 3A5, the structure of 3A5 complexed with ritonavir was determined by X-ray crystallography to a limiting resolution of 2.91 Å. The secondary and tertiary structures of 3A5 and 3A4 are similar, but the architectures of their active sites differ. The 3A5 active site is taller and narrower than that of 3A4. As a result, ritonavir adopts a distinctly different conformation to fit into the cavity of 3A5 than seen for 3A4. These structural changes reflect amino acid differences that alter the conformation of the helix F through helix G region in the upper portion of the cavity and ionic interactions between residues in the beta-sheet domain that reduce the width of the cavity. The structural differences exhibited by 3A4 and 3A5 suggest that the overlap of catalytic activities may reflect molecular flexibility that determines how alternative conformers fit into the different active site architectures of the two enzymes.

PubMed: 29093019
DOI: 10.1124/mol.117.109744

実験手法

X-RAY DIFFRACTION (2.91 Å)