Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 60, Issue 6, Pages 3131-3137Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202011793
Keywords
cryo-electron microscopy; inhibitors; nanodiscs; structural biology; voltage-gated calcium ion channels
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Funding
- Princeton Center for Complex Materials, a National Science Foundation (NSF)-MRSEC program [DMR-1420541]
- NIH [5R01GM130762]
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This study reports the structures of Ca(v)1.1 bound with different drugs, revealing the molecular basis for their effects. The structures show that amlodipine and nifedipine have different impacts on Ca(v)1.1, while the two enantiomers of Bay K8644 as agonists are insufficient to maintain the activated state of the channel.
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 angstrom. 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.
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