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- PDB-8we8: Human L-type voltage-gated calcium channel Cav1.2 in the presence... -
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Basic information
Entry | Database: PDB / ID: 8we8 | ||||||
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Title | Human L-type voltage-gated calcium channel Cav1.2 in the presence of calciseptine, amlodipine and pinaverium at 2.9 Angstrom resolution | ||||||
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![]() | MEMBRANE PROTEIN / Cav1.2 / Channels / Calcium Ion-Selective / TRANSPORT PROTEIN | ||||||
Function / homology | ![]() voltage-gated calcium channel activity involved in AV node cell action potential / voltage-gated calcium channel activity involved in cardiac muscle cell action potential / immune system development / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / membrane depolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of muscle contraction ...voltage-gated calcium channel activity involved in AV node cell action potential / voltage-gated calcium channel activity involved in cardiac muscle cell action potential / immune system development / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / membrane depolarization during atrial cardiac muscle cell action potential / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / positive regulation of muscle contraction / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / positive regulation of adenylate cyclase activity / high voltage-gated calcium channel activity / cardiac conduction / L-type voltage-gated calcium channel complex / membrane depolarization during cardiac muscle cell action potential / cell communication by electrical coupling involved in cardiac conduction / regulation of ventricular cardiac muscle cell action potential / cardiac muscle cell action potential involved in contraction / camera-type eye development / NCAM1 interactions / regulation of ventricular cardiac muscle cell membrane repolarization / embryonic forelimb morphogenesis / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / voltage-gated calcium channel complex / neuromuscular junction development / calcium ion import across plasma membrane / Phase 0 - rapid depolarisation / neuronal dense core vesicle / regulation of heart rate by cardiac conduction / alpha-actinin binding / regulation of calcium ion transport / calcium channel regulator activity / voltage-gated calcium channel activity / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / sarcoplasmic reticulum / protein localization to plasma membrane / Regulation of insulin secretion / calcium ion transmembrane transport / postsynaptic density membrane / Z disc / Adrenaline,noradrenaline inhibits insulin secretion / cellular response to amyloid-beta / calcium ion transport / heart development / T cell receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / toxin activity / chemical synaptic transmission / perikaryon / postsynaptic density / calmodulin binding / synapse / dendrite / extracellular exosome / extracellular region / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 Å | ||||||
![]() | Gao, S. / Yao, X. / Yan, N. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structural basis for human Ca1.2 inhibition by multiple drugs and the neurotoxin calciseptine. Authors: Shuai Gao / Xia Yao / Jiaofeng Chen / Gaoxingyu Huang / Xiao Fan / Lingfeng Xue / Zhangqiang Li / Tong Wu / Yupeng Zheng / Jian Huang / Xueqin Jin / Yan Wang / Zhifei Wang / Yong Yu / Lei ...Authors: Shuai Gao / Xia Yao / Jiaofeng Chen / Gaoxingyu Huang / Xiao Fan / Lingfeng Xue / Zhangqiang Li / Tong Wu / Yupeng Zheng / Jian Huang / Xueqin Jin / Yan Wang / Zhifei Wang / Yong Yu / Lei Liu / Xiaojing Pan / Chen Song / Nieng Yan / ![]() ![]() Abstract: Ca1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca1.2, both in its apo form and in complex with several drugs, as well ...Ca1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSD. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Na channels, a series of structural changes occur, including upward movement of VSD coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5 merges with S5 to become a single helix, resulting in a widened but still non-conductive intracellular gate. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 567.2 KB | Display | ![]() |
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PDB format | ![]() | 438.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 37474MC ![]() 8fhsC ![]() 8we6C ![]() 8we7C ![]() 8we9C ![]() 8weaC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Voltage-dependent L-type calcium channel subunit ... , 2 types, 2 molecules AC
#1: Protein | Mass: 246851.250 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#3: Protein | Mass: 54607.852 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Protein , 2 types, 2 molecules DB
#2: Protein | Mass: 124692.469 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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#4: Protein | Mass: 7056.273 Da / Num. of mol.: 1 / Source method: obtained synthetically Source: (synth.) ![]() References: UniProt: P22947 |
-Sugars , 4 types, 8 molecules ![](data/chem/img/NAG.gif)
#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 Source method: isolated from a genetically manipulated source | ||||
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#6: Polysaccharide | Source method: isolated from a genetically manipulated source #7: 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-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose | Source method: isolated from a genetically manipulated source #10: Sugar | |
-Non-polymers , 5 types, 10 molecules ![](data/chem/img/CA.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/PT5.gif)
![](data/chem/img/3PE.gif)
![](data/chem/img/6UB.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/PT5.gif)
![](data/chem/img/3PE.gif)
![](data/chem/img/6UB.gif)
#8: Chemical | #9: Chemical | ChemComp-CLR / #11: Chemical | ChemComp-PT5 / [( | #12: Chemical | ChemComp-3PE / | #13: Chemical | ChemComp-6UB / | |
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-Details
Has ligand of interest | N |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Cav1.2 / Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
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 |
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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: ![]() |
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) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 118337 / Symmetry type: POINT | ||||||||||||||||||||||||
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