8E58

Rabbit L-type voltage-gated calcium channel Cav1.1 in the presence of Amiodarone and 1 mM MNI-1 at 3.0 Angstrom resolution

Summary for 8E58

• Entry DOI: 10.2210/pdb8e58/pdb
• EMDB information: 27906
• Related PRD ID: PRD_900017
• Descriptor: Voltage-dependent L-type calcium channel subunit alpha-1S, 2-acetamido-2-deoxy-beta-D-glucopyranose, Voltage-dependent calcium channel gamma-1 subunit, ... (10 entities in total)
• Functional Keywords: cav1.1, channels, calcium ion-selective, transport protein
• Biological source: Oryctolagus cuniculus (rabbit); More
• Total number of polymer chains: 3
• Total formula weight: 368800.52

Authors

Gao, S.,Yao, X.,Yan, N. (deposition date: 2022-08-20, release date: 2022-12-07, Last modification date: 2024-10-23)

Primary citation

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.
Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca v channels.
Cell, 185:4801-4810.e13, 2022

PubMed Abstract: 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 channels, but the molecular mechanism has remained unclear. Here we present systematic cryo-EM structural analysis of Ca1.1 and Ca1.3 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 channels.

PubMed: 36417914
DOI: 10.1016/j.cell.2022.10.024

Experimental method

ELECTRON MICROSCOPY (3 Å)