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- PDB-8fhs: Human L-type voltage-gated calcium channel Cav1.2 in the presence... -

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Basic information

Entry
Database: PDB / ID: 8fhs
TitleHuman L-type voltage-gated calcium channel Cav1.2 in the presence of amiodarone and sofosbuvir at 3.3 Angstrom resolution
Components
  • (Voltage-dependent L-type calcium channel subunit ...) x 2
  • Voltage-dependent calcium channel subunit alpha-2/delta-1
KeywordsTRANSPORT PROTEIN / Cav1.2 / Channels / Calcium Ion-Selective
Function / homology
Function and homology information


positive regulation of high voltage-gated calcium channel activity / 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 / positive regulation of adenylate cyclase activity / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / membrane depolarization during atrial cardiac muscle cell action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / Phase 2 - plateau phase ...positive regulation of high voltage-gated calcium channel activity / 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 / positive regulation of adenylate cyclase activity / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / membrane depolarization during atrial cardiac muscle cell action potential / calcium ion transmembrane transport via high voltage-gated calcium channel / Phase 2 - plateau phase / high voltage-gated calcium channel activity / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / cardiac conduction / L-type voltage-gated calcium channel complex / membrane depolarization during cardiac muscle cell action potential / positive regulation of muscle contraction / cell communication by electrical coupling involved in cardiac conduction / regulation of ventricular cardiac muscle cell action potential / regulation of ventricular cardiac muscle cell membrane repolarization / NCAM1 interactions / camera-type eye development / cardiac muscle cell action potential involved in contraction / 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 / Mechanical load activates signaling by PIEZO1 and integrins in osteocytes / Phase 0 - rapid depolarisation / alpha-actinin binding / regulation of heart rate by cardiac conduction / calcium ion import across plasma membrane / regulation of calcium ion transport / neuronal dense core vesicle / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / voltage-gated calcium channel activity / presynaptic active zone membrane / sarcoplasmic reticulum / protein localization to plasma membrane / calcium channel regulator activity / Regulation of insulin secretion / postsynaptic density membrane / GABA-ergic synapse / calcium ion transmembrane transport / Z disc / cellular response to amyloid-beta / Adrenaline,noradrenaline inhibits insulin secretion / calcium ion transport / T cell receptor signaling pathway / heart development / positive regulation of cytosolic calcium ion concentration / perikaryon / chemical synaptic transmission / calmodulin binding / postsynaptic density / cilium / dendrite / synapse / extracellular exosome / nucleoplasm / metal ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Voltage-dependent calcium channel, L-type, beta-3 subunit / Voltage-dependent L-type calcium channel subunit beta-3, SH3 domain / Voltage-dependent calcium channel, L-type, alpha-1C subunit / Voltage-dependent calcium channel, L-type, beta subunit / Voltage-dependent L-type calcium channel subunit beta-1-4, N-terminal A domain / Voltage gated calcium channel subunit beta domain 4Aa N terminal / Voltage-gated calcium channel subunit alpha, C-terminal / Voltage-gated calcium channel subunit alpha, C-term / Voltage-dependent calcium channel, L-type, alpha-1 subunit / VWA N-terminal ...Voltage-dependent calcium channel, L-type, beta-3 subunit / Voltage-dependent L-type calcium channel subunit beta-3, SH3 domain / Voltage-dependent calcium channel, L-type, alpha-1C subunit / Voltage-dependent calcium channel, L-type, beta subunit / Voltage-dependent L-type calcium channel subunit beta-1-4, N-terminal A domain / Voltage gated calcium channel subunit beta domain 4Aa N terminal / Voltage-gated calcium channel subunit alpha, C-terminal / Voltage-gated calcium channel subunit alpha, C-term / Voltage-dependent calcium channel, L-type, alpha-1 subunit / VWA N-terminal / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / VWA N-terminal / Neuronal voltage-dependent calcium channel alpha 2acd / : / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain / Voltage gated calcium channel IQ domain / Voltage gated calcium channel IQ domain / Voltage-dependent calcium channel, alpha-1 subunit / Voltage-dependent L-type calcium channel, IQ-associated domain / Voltage-dependent L-type calcium channel, IQ-associated / : / Guanylate kinase/L-type calcium channel beta subunit / Guanylate kinase / Guanylate kinase homologues. / von Willebrand factor type A domain / VWFA domain profile. / von Willebrand factor (vWF) type A domain / Voltage-dependent channel domain superfamily / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Ion transport domain / Ion transport protein / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
1,2-Distearoyl-sn-glycerophosphoethanolamine / Chem-BBI / CHOLESTEROL / Sofosbuvir / Voltage-dependent L-type calcium channel subunit beta-3 / Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent L-type calcium channel subunit alpha-1C
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsGao, S. / Yao, X. / Yan, N.
Funding support China, 1items
OrganizationGrant numberCountry
Other privateZ191100001119127 China
CitationJournal: Cell / Year: 2023
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
DepositionDec 15, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 13, 2023Provider: repository / Type: Initial release
Revision 1.0Dec 13, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 13, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Dec 13, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Dec 13, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Dec 13, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 13, 2023Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.2Jun 4, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 4, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Voltage-dependent L-type calcium channel subunit alpha-1C
D: Voltage-dependent calcium channel subunit alpha-2/delta-1
C: Voltage-dependent L-type calcium channel subunit beta-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)436,01420
Polymers428,5433
Non-polymers7,47217
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Voltage-dependent L-type calcium channel subunit ... , 2 types, 2 molecules AC

#1: Protein Voltage-dependent L-type calcium channel subunit alpha-1C / Calcium channel / L type / alpha-1 polypeptide / isoform 1 / cardiac muscle / Voltage-gated calcium ...Calcium channel / L type / alpha-1 polypeptide / isoform 1 / cardiac muscle / Voltage-gated calcium channel subunit alpha Cav1.2


Mass: 249242.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA1C, CACH2, CACN2, CACNL1A1, CCHL1A1 / Production host: Homo sapiens (human) / References: UniProt: Q13936
#3: Protein Voltage-dependent L-type calcium channel subunit beta-3 / CAB3 / Calcium channel voltage-dependent subunit beta 3


Mass: 54607.852 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNB3, CACNLB3 / Production host: Homo sapiens (human) / References: UniProt: P54284

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Protein , 1 types, 1 molecules D

#2: Protein Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-gated calcium channel subunit alpha-2/delta-1


Mass: 124692.469 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA2D1, CACNL2A, CCHL2A, MHS3 / Production host: Homo sapiens (human) / References: UniProt: P54289

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Sugars , 4 types, 7 molecules

#4: 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


Type: oligosaccharide / Mass: 627.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,3,2/[a2122h-1b_1-5_2*NCC/3=O]/1-1-1/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}LINUCSPDB-CARE
#5: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#6: 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


Type: oligosaccharide / Mass: 830.786 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,4,3/[a2122h-1b_1-5_2*NCC/3=O]/1-1-1-1/a4-b1_b4-c1_c4-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}}}LINUCSPDB-CARE
#12: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 5 types, 10 molecules

#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-BBI / (2-butyl-1-benzofuran-3-yl){4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl}methanone


Mass: 645.312 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H29I2NO3 / Feature type: SUBJECT OF INVESTIGATION
#9: Chemical ChemComp-WG6 / Sofosbuvir


Mass: 529.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29FN3O9P / Feature type: SUBJECT OF INVESTIGATION
#10: Chemical ChemComp-3PE / 1,2-Distearoyl-sn-glycerophosphoethanolamine / 3-SN-PHOSPHATIDYLETHANOLAMINE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 748.065 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H82NO8P / Comment: phospholipid*YM
#11: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C27H46O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cav1.2 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2100 nm / Nominal defocus min: 1900 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 88794 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00421429
ELECTRON MICROSCOPYf_angle_d0.56729038
ELECTRON MICROSCOPYf_dihedral_angle_d8.9822960
ELECTRON MICROSCOPYf_chiral_restr0.0423317
ELECTRON MICROSCOPYf_plane_restr0.0043639

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