Structural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Ca_v 1.1 by Dihydropyridine Compounds*.

ABSTRACT: 1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca²⁺ (Ca_v ) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. The structure of rabbit Ca_v 1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remained elusive. Herein, we report five cryo-EM structures of nanodisc-embedded Ca_v 1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (R)-(+)-Bay K8644, and a titration of its agonistic enantiomer (S)-(-)-Bay K8644 at resolutions of 2.9-3.4?Å. The amlodipine-bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that (S)-(-)-Bay K8644, when acting as an agonist, is insufficient to lock the activated state of the channel for a prolonged duration.

SUBMITTER: Gao S 

PROVIDER: S-EPMC7898392 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature