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

Molecular Pharmacology
Lin TangWilliam A Catterall

Abstract

Diltiazem is a widely prescribed Ca2+ antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral CaV channel construct CaVAb 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 and presence of amlodipine. The binding pose in the presence of amlodipine may mimic a high-affinity binding configuration induced by voltage-dependent inactivation, which is favored by dihydropyridine binding. In this binding pose, the tertiary amino group of diltiazem projects upward into the inner end of the ion selectivity filter, interacts with ion coordination Site 3 formed by the backbone carbonyls of T175, and alters binding of Ca2+ to ion coordination Sites 1 and 2. Altogether, our results define the receptor...Continue Reading

References

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Citations

Aug 20, 2020·The Journal of International Medical Research·YaNan GaoBaiDong Li
Sep 21, 2019·Annual Review of Pharmacology and Toxicology·William A CatterallTamer M Gamal El-Din
Jul 10, 2020·Proceedings of the National Academy of Sciences of the United States of America·Martin T JohnsonMohamed Trebak
Aug 8, 2021·International Journal of Molecular Sciences·Denis B Tikhonov, Boris S Zhorov

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