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TitleStructural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca channels.
Journal, issue, pagesCell, Vol. 185, Issue 25, Page 4801-4810.e13, Year 2022
Publish dateDec 8, 2022
AuthorsXia Yao / Shuai Gao / Jixin Wang / Zhangqiang Li / Jian Huang / Yan Wang / Zhifei Wang / Jiaofeng Chen / Xiao Fan / Weipeng Wang / Xueqin Jin / Xiaojing Pan / Yong Yu / Armando Lagrutta / Nieng Yan /
PubMed AbstractDrug-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 ...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.
External linksCell / PubMed:36417914 / PubMed Central
MethodsEM (single particle)
Resolution2.8 - 3.3 Å
Structure data

27904

8e56

EMDB-27904, PDB-8e56:
Rabbit L-type voltage-gated calcium channel Cav1.1 in the presence of Amiodarone at 2.8 Angstrom resolution
Method: EM (single particle) / Resolution: 2.8 Å

27905

8e57

EMDB-27905, PDB-8e57:
Rabbit L-type voltage-gated calcium channel Cav1.1 in the presence of Amiodarone and 100 microM MNI-1 at 2.8 Angstrom resolution
Method: EM (single particle) / Resolution: 2.8 Å

27906

8e58

EMDB-27906, PDB-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
Method: EM (single particle) / Resolution: 3.0 Å

27907

8e59

EMDB-27907, PDB-8e59:
Human L-type voltage-gated calcium channel Cav1.3 in the presence of Amiodarone at 3.1 Angstrom resolution
Method: EM (single particle) / Resolution: 3.1 Å

27908

8e5a

EMDB-27908, PDB-8e5a:
Human L-type voltage-gated calcium channel Cav1.3 treated with 1.4 mM Sofosbuvir at 3.3 Angstrom resolution
Method: EM (single particle) / Resolution: 3.3 Å

27909

8e5b

EMDB-27909, PDB-8e5b:
Human L-type voltage-gated calcium channel Cav1.3 in the presence of Amiodarone and Sofosbuvir at 3.3 Angstrom resolution
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-BBI:
(2-butyl-1-benzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl}methanone / medication, antiarrhythmic*YM

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-WFR:
propan-2-yl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-ethynyl-3-hydroxy-4-methyloxolan-2-yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (non-preferred name)

ChemComp-WG6:
Sofosbuvir / medication*YM

Source
  • oryctolagus cuniculus (rabbit)
  • rabbit (rabbit)
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Cav1.1 / Channels / Calcium Ion-Selective / Cav1.3

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