Structural Basis of the Modulation of the Voltage‐Gated Calcium Ion Channel Ca v 1.1 by Dihydropyridine Compounds**
Year: 2020
Type: article
Abstract: 1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca 2+ (Ca v ) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. Recent structural elucidation 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 remains elusive. Here, 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 the agonistic effect of (S)-(-)-Bay K8644 might be transient. The similarity of these structures to that obtained in detergent micelles alleviates the concerns about potential structural perturbation by detergents.
Source: Angewandte Chemie
Authors: Shuai Gao, Nieng Yan
Institution: Princeton University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
OpenAlex ID: W4236931740