7jpl
From Proteopedia
Rabbit Cav1.1 in the presence of 10 micromolar (S)-(-)-Bay K8644 in nanodiscs at 3.4 Angstrom resolution
Structural highlights
FunctionCCG1_RABIT This protein is a subunit of the dihydropyridine (DHP) sensitive calcium channel. Plays a role in excitation-contraction coupling. The skeletal muscle DHP-sensitive Ca(2+) channel may function only as a multiple subunit complex. Publication Abstract from PubMed1,4-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. 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 A. 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. Structural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Ca(v) 1.1 by Dihydropyridine Compounds*.,Gao S, Yan N Angew Chem Int Ed Engl. 2021 Feb 8;60(6):3131-3137. doi: 10.1002/anie.202011793. , Epub 2020 Dec 10. PMID:33125829[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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