8VZ7

Crystal Structure of Human Cytochrome P450 2C9*27 (R150L) Genetic Variant in Complex with the Drug Losartan

8VZ7 の概要

• エントリーDOI: 10.2210/pdb8vz7/pdb
• 分子名称: Cytochrome P450 2C9, PROTOPORPHYRIN IX CONTAINING FE, [2-butyl-5-chloranyl-3-[[4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol, ... (6 entities in total)
• 機能のキーワード: cytochrome p450 2c9*27 genetic variant, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55873.34

構造登録者

Shah, M.B. (登録日: 2024-02-11, 公開日: 2024-06-12, 最終更新日: 2024-06-26)

主引用文献

Parikh, S.J.,Edara, S.,Deodhar, S.,Singh, A.K.,Maekawa, K.,Zhang, Q.,Glass, K.C.,Shah, M.B.
Structural and biophysical analysis of cytochrome P450 2C9*14 and *27 variants in complex with losartan.
J.Inorg.Biochem., 258:112622-112622, 2024

PubMed Abstract: The human cytochrome P450 (CYP) 1, 2 and 3 families of enzymes are responsible for the biotransformation of a majority of the currently available pharmaceutical drugs. The highly polymorphic CYP2C9 predominantly metabolizes many drugs including anticoagulant S-warfarin, anti-hypertensive losartan, anti-diabetic tolbutamide, analgesic ibuprofen, etc. There are >80 single nucleotide changes identified in CYP2C9, many of which significantly alter the clearance of important drugs. Here we report the structural and biophysical analysis of two polymorphic variants, CYP2C9*14 (Arg125His) and CYP2C9*27 (Arg150Leu) complexed with losartan. The X-ray crystal structures of the CYP2C9*14 and *27 illustrate the binding of two losartan molecules, one in the active site near heme and another on the periphery. Both losartan molecules are bound in an identical conformation to that observed in the previously solved CYP2C9 wild-type complex, however, the number of losartan differs from the wild-type structure, which showed binding of three molecules. Additionally, isothermal titration calorimetry experiments reveal a lower binding affinity of losartan with *14 and *27 variants when compared to the wild-type. Overall, the results provide new insights into the effects of these genetic polymorphisms and suggests a possible mechanism contributing to reduced metabolic activity in patients carrying these alleles.

PubMed: 38852293
DOI: 10.1016/j.jinorgbio.2024.112622

実験手法

X-RAY DIFFRACTION (2.53 Å)