7JPW

Rabbit Cav1.1 in the presence of 100 micromolar (R)-(+)-Bay K8644 in nanodiscs at 3.2 Angstrom resolution

Summary for 7JPW

• Entry DOI: 10.2210/pdb7jpw/pdb
• EMDB information: 22414 22415 22424 22425 22426
• Descriptor: Voltage-dependent L-type calcium channel subunit alpha-1S, Voltage-dependent calcium channel gamma-1 subunit, Voltage-dependent calcium channel subunit alpha-2/delta-1, ... (7 entities in total)
• Functional Keywords: rcav1.1, channels, calcium ion-selective, transport protein, drugs
• Biological source: Oryctolagus cuniculus (Rabbit); More
• Total number of polymer chains: 3
• Total formula weight: 370325.87

Authors

Yan, N.,Gao, S. (deposition date: 2020-08-10, release date: 2020-11-18, Last modification date: 2025-05-14)

Primary citation

Gao, S.,Yan, N.
Structural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Ca v 1.1 by Dihydropyridine Compounds*.
Angew.Chem.Int.Ed.Engl., 60:3131-3137, 2021

PubMed Abstract: 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.

PubMed: 33125829
DOI: 10.1002/anie.202011793

Experimental method

ELECTRON MICROSCOPY (3.2 Å)