8e57
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[8e57]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8E57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E57 FirstGlance]. <br> | <table><tr><td colspan='2'>[[8e57]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Oryctolagus_cuniculus Oryctolagus cuniculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8E57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8E57 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BBI:(2-BUTYL-1-BENZOFURAN-3-YL){4-[2-(DIETHYLAMINO)ETHOXY]-3,5-DIIODOPHENYL}METHANONE'>BBI</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PRD_900017:triacetyl-beta-chitotriose'>PRD_900017</scene>, <scene name='pdbligand=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)'>WFR</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.8Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BBI:(2-BUTYL-1-BENZOFURAN-3-YL){4-[2-(DIETHYLAMINO)ETHOXY]-3,5-DIIODOPHENYL}METHANONE'>BBI</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PRD_900017:triacetyl-beta-chitotriose'>PRD_900017</scene>, <scene name='pdbligand=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)'>WFR</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8e57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e57 OCA], [https://pdbe.org/8e57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e57 RCSB], [https://www.ebi.ac.uk/pdbsum/8e57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e57 ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8e57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8e57 OCA], [https://pdbe.org/8e57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8e57 RCSB], [https://www.ebi.ac.uk/pdbsum/8e57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8e57 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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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. | 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 | + | 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<ref>PMID:36417914</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 8e57" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 8e57" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Ion channels 3D structures|Ion channels 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Rabbit L-type voltage-gated calcium channel Cav1.1 in the presence of Amiodarone and 100 microM MNI-1 at 2.8 Angstrom resolution
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