8e59

Human L-type voltage-gated calcium channel Cav1.3 in the presence of Amiodarone at 3.1 Angstrom resolution

spinqualitylabelsall models 8e59, resolution 3.10Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8e59 is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.1Å Ligands: 3PE, BBI, CA, NAG, PRD_900017 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function CAC1D_HUMAN 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-1D 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). Publication Abstract from PubMed Drug-drug interaction of the antiviral sofosbuvir and the antiarrhythmics amiodarone has been reported to cause fatal heartbeat slowing. Sofosbuvir and its analog, MNI-1, were reported to potentiate the inhibition of cardiomyocyte calcium handling by amiodarone, which functions as a multi-channel antagonist, and implicate its inhibitory effect on L-type Ca(v) channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Ca(v)1.1 and Ca(v)1.3 treated with amiodarone or sofosbuvir alone, or sofosbuvir/MNI-1 combined with amiodarone. Whereas amiodarone alone occupies the dihydropyridine binding site, sofosbuvir is not found in the channel when applied on its own. In the presence of amiodarone, sofosbuvir/MNI-1 is anchored in the central cavity of the pore domain through specific interaction with amiodarone and directly obstructs the ion permeation path. Our study reveals the molecular basis for the physical, pharmacodynamic interaction of two drugs on the scaffold of Ca(v) channels. Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca(v) channels.,Yao X, Gao S, Wang J, Li Z, Huang J, Wang Y, Wang Z, Chen J, Fan X, Wang W, Jin X, Pan X, Yu Y, Lagrutta A, Yan N Cell. 2022 Dec 8;185(25):4801-4810.e13. doi: 10.1016/j.cell.2022.10.024. Epub , 2022 Nov 22. PMID:36417914 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ion channels 3D structures

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