Structural Basis for Diltiazem Block of a Voltage-Gated Ca²⁺ Channel.

ABSTRACT: Diltiazem is a widely prescribed Ca²⁺ antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral Ca_V channel construct Ca_VAb as a molecular model for X-ray crystallographic analysis, we show here that diltiazem targets the central cavity of the voltage-gated Ca²⁺ channel underneath its selectivity filter and physically blocks ion conduction. The diltiazem-binding site overlaps with the receptor site for phenylalkylamine Ca²⁺ antagonist drugs such as verapamil. The dihydropyridine Ca²⁺ channel blocker amlodipine binds at a distinct site and allosterically modulates the binding sites for diltiazem and Ca²⁺ Our studies resolve two distinct binding poses for diltiazem in the absence

SUBMITTER: Tang L 

PROVIDER: S-EPMC6738535 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature