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Yorodumi- PDB-8e57: Rabbit L-type voltage-gated calcium channel Cav1.1 in the presenc... -
+Open data
-Basic information
Entry | Database: PDB / ID: 8.0E+57 | ||||||
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Title | Rabbit L-type voltage-gated calcium channel Cav1.1 in the presence of Amiodarone and 100 microM MNI-1 at 2.8 Angstrom resolution | ||||||
Components |
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Keywords | TRANSPORT PROTEIN / Cav1.1 / Channels / Calcium Ion-Selective | ||||||
Function / homology | Function and homology information positive regulation of muscle contraction / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / calcium ion import across plasma membrane / cellular response to caffeine / calcium channel regulator activity / regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated calcium channel activity / muscle contraction ...positive regulation of muscle contraction / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / calcium ion import across plasma membrane / cellular response to caffeine / calcium channel regulator activity / regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated calcium channel activity / muscle contraction / release of sequestered calcium ion into cytosol / T-tubule / calcium ion transmembrane transport / sarcolemma / transmembrane transporter binding / calmodulin binding / metal ion binding / plasma membrane Similarity search - Function | ||||||
Biological species | Oryctolagus cuniculus (rabbit) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å | ||||||
Authors | Gao, S. / Yao, X. / Yan, N. | ||||||
Funding support | United States, 1items
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Citation | Journal: Cell / Year: 2022 Title: Structural basis for the severe adverse interaction of sofosbuvir and amiodarone on L-type Ca channels. Authors: Xia 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 / 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 ...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. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8e57.cif.gz | 487.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8e57.ent.gz | 380.1 KB | Display | PDB format |
PDBx/mmJSON format | 8e57.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8e57_validation.pdf.gz | 1.9 MB | Display | wwPDB validaton report |
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Full document | 8e57_full_validation.pdf.gz | 2 MB | Display | |
Data in XML | 8e57_validation.xml.gz | 68.6 KB | Display | |
Data in CIF | 8e57_validation.cif.gz | 102.1 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/e5/8e57 ftp://data.pdbj.org/pub/pdb/validation_reports/e5/8e57 | HTTPS FTP |
-Related structure data
Related structure data | 27905MC 8e56C 8e58C 8e59C 8e5aC 8e5bC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Protein , 1 types, 1 molecules A
#1: Protein | Mass: 212240.594 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P07293 |
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-Voltage-dependent calcium channel ... , 2 types, 2 molecules EF
#2: Protein | Mass: 25082.254 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P19518 |
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#3: Protein | Mass: 125169.984 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P13806 |
-Sugars , 4 types, 14 molecules
#4: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose Source method: isolated from a genetically manipulated source #5: Polysaccharide | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2- ...2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose | #6: Polysaccharide | Source method: isolated from a genetically manipulated source #10: Sugar | ChemComp-NAG / |
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-Non-polymers , 3 types, 4 molecules
#7: Chemical | #8: Chemical | ChemComp-BBI / ( | #9: Chemical | ChemComp-WFR / | |
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-Details
Has ligand of interest | Y |
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Has protein modification | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Cav1.1 / Type: COMPLEX / Entity ID: #1-#3 / Source: NATURAL |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: Oryctolagus cuniculus (rabbit) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2100 nm / Nominal defocus min: 1900 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction | Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 190835 / Symmetry type: POINT | ||||||||||||||||||||||||
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