7RL2

Crystal Structure of the Human Cytochrome P450 2C9*8 (CYP2C9*8) Genetic Variant in Complex with the Drug Losartan

7RL2 の概要

• エントリーDOI: 10.2210/pdb7rl2/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, cyp2c9, 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: 55813.14

構造登録者

Shah, M.B. (登録日: 2021-07-23, 公開日: 2021-10-06, 最終更新日: 2023-10-18)

主引用文献

Parikh, S.J.,Kamat, S.,Phillips, M.,Boyson, S.P.,Yarbrough, T.,Davie, D.,Zhang, Q.,Glass, K.C.,Shah, M.B.
Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison.
Int J Mol Sci, 22:-, 2021

PubMed Abstract: Cytochromes P450 (CYP) are one of the major xenobiotic metabolizing enzymes with increasing importance in pharmacogenetics. The CYP2C9 enzyme is responsible for the metabolism of a wide range of clinical drugs. More than sixty genetic variations have been identified in CYP2C9 with many demonstrating reduced activity compared to the wild-type (WT) enzyme. The CYP2C9*8 allele is predominantly found in persons of African ancestry and results in altered clearance of several drug substrates of CYP2C9. The X-ray crystal structure of CYP2C9*8, which represents an amino acid variation from arginine to histidine at position 150 (R150H), was solved in complex with losartan. The overall conformation of the CYP2C9*8-losartan complex was similar to the previously solved complex with wild type (WT) protein, but it differs in the occupancy of losartan. One molecule of losartan was bound in the active site and another on the surface in an identical orientation to that observed in the WT complex. However, unlike the WT structure, the losartan in the access channel was not observed in the *8 complex. Furthermore, isothermal titration calorimetry studies illustrated weaker binding of losartan to *8 compared to WT. Interestingly, the CYP2C9*8 interaction with losartan was not as weak as the CYP2C9*3 variant, which showed up to three-fold weaker average dissociation constant compared to the WT. Taken together, the structural and solution characterization yields insights into the similarities and differences of losartan binding to CYP2C9 variants and provides a useful framework for probing the role of amino acid substitution and substrate dependent activity.

PubMed: 34638547
DOI: 10.3390/ijms221910206

実験手法

X-RAY DIFFRACTION (2.23 Å)