Structural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Cav1.1 by Dihydropyridine Compounds**

Shuai Gao, Nieng Yan

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca2+ (Cav) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. The structure of rabbit Cav1.1 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 Cav1.1 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.

Original languageEnglish (US)
Pages (from-to)3131-3137
Number of pages7
JournalAngewandte Chemie - International Edition
Volume60
Issue number6
DOIs
StatePublished - Feb 8 2021

All Science Journal Classification (ASJC) codes

  • Catalysis
  • Chemistry(all)

Keywords

  • cryo-electron microscopy
  • inhibitors
  • nanodiscs
  • structural biology
  • voltage-gated calcium ion channels

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