Structural Basis of Single-Nucleotide Polymorphisms in Cytochrome P450 2C9.

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

SUBMITTER: Maekawa K 

PROVIDER: S-EPMC5761073 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature