7jpk

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Rabbit Cav1.1 in the presence of 100 micromolar (S)-(-)-Bay K8644 in nanodiscs at 3.0 Angstrom resolution

Structural highlights

7jpk is a 3 chain structure with sequence from Oryctolagus cuniculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CAC1S_RABIT Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle.

Publication Abstract from PubMed

1,4-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.

References

↑ 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. 2021 Feb 8;60(6):3131-3137. PMID:33125829 doi:10.1002/anie.202011793