5X23

Crystal structure of CYP2C9 genetic variant A477T (*30) in complex with multiple losartan molecules

Summary for 5X23

• Entry DOI: 10.2210/pdb5x23/pdb
• Related: 5X24
• Descriptor: 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)
• Functional Keywords: oxidoreductase, cyp2c9 polymorphic mutant, single nucleotide polymorphism, p450 2c9 genetic variant
• Biological source: Homo sapiens (Human)
• Cellular location: Endoplasmic reticulum membrane; Peripheral membrane protein: P11712
• Total number of polymer chains: 1
• Total formula weight: 56285.13

Authors

Maekawa, K.,Adachi, M.,Shah, M.B. (deposition date: 2017-01-30, release date: 2017-10-25, Last modification date: 2023-11-22)

Primary citation

Maekawa, K.,Adachi, M.,Matsuzawa, Y.,Zhang, Q.,Kuroki, R.,Saito, Y.,Shah, M.B.
Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9
Biochemistry, 56:5476-5480, 2017

PubMed Abstract: Single-nucleotide polymorphisms in drug-metabolizing cytochrome P450 (CYP) enzymes are important contributors to interindividual differences in drug metabolism leading to adverse drug reactions. Despite their extensive characterization and importance in pharmacogenetics of clinical drugs, the structural basis of CYP polymorphisms has remained scant. Here we report the crystal structures of human CYP2C9 and its polymorphic variants, *3 (I359L) and *30 (A477T), with an antihypertensive drug losartan. The structures show distinct interaction and occupation of losartan in the active site, the access channel, and the peripheral binding site. The I359L substitution located far from the active site remarkably altered the residue side chains near the active site and the access channel, whereas the T477 substitution illustrated hydrogen-bonding interaction with the reoriented side chain of Q214. The results yield structural insights into the reduced catalytic activity of the CYP2C9 variants and have important implications for understanding genetic polymorphisms in CYP-mediated drug metabolism.

PubMed: 28972767
DOI: 10.1021/acs.biochem.7b00795

Experimental method

X-RAY DIFFRACTION (2 Å)