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

TitleStructural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Ca 1.1 by Dihydropyridine Compounds*.
Publication TypeJournal Article
Year of Publication2021
AuthorsGao, S, Yan, N
JournalAngew Chem Int Ed Engl
Volume60
Issue6
Pagination3131-3137
Date Published2021 02 08
ISSN1521-3773
Keywords3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester, Amlodipine, Binding Sites, Calcium Channel Agonists, Calcium Channel Blockers, Calcium Channels, L-Type, Cryoelectron Microscopy, Dihydropyridines, Molecular Dynamics Simulation, Nanostructures, Protein Structure, Tertiary, Stereoisomerism
Abstract

<p>1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca (Ca ) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. The structure of rabbit Ca 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 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.</p>

DOI10.1002/anie.202011793
Alternate JournalAngew Chem Int Ed Engl
PubMed ID33125829
PubMed Central IDPMC7898392
Grant ListR01 GM130762 / GM / NIGMS NIH HHS / United States
5R01GM130762 / NH / NIH HHS / United States