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- PDB-8fd7: Structure of the human L-type voltage-gated calcium channel Cav1.... -

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Basic information

Entry
Database: PDB / ID: 8fd7
TitleStructure of the human L-type voltage-gated calcium channel Cav1.2 complexed with gabapentin
Components
  • (Voltage-dependent L-type calcium channel subunit ...) x 2
  • Voltage-dependent calcium channel subunit alpha-2/delta-1
KeywordsMEMBRANE PROTEIN / voltage-gated calcium channel / CaV alpha2delta / drug binding / gabapentin
Function / homology
Function and homology information


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 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 / positive regulation of adenylate cyclase 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 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 / 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 / calcium ion transport into cytosol / embryonic forelimb morphogenesis / voltage-gated calcium channel complex / calcium ion import across plasma membrane / Phase 0 - rapid depolarisation / alpha-actinin binding / regulation of heart rate by cardiac conduction / calcium channel regulator activity / voltage-gated calcium channel activity / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / T-tubule / Regulation of insulin secretion / calcium ion transmembrane transport / postsynaptic density membrane / Z disc / Adrenaline,noradrenaline inhibits insulin secretion / heart development / positive regulation of cytosolic calcium ion concentration / perikaryon / postsynaptic density / calmodulin binding / dendrite / membrane / metal ion binding / plasma membrane / cytoplasm
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 / von Willebrand factor (vWF) type A domain / VWFA domain profile. / 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
CHOLESTEROL / [1-(AMINOMETHYL)CYCLOHEXYL]ACETIC ACID / Chem-WO9 / Chem-YSW / Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent L-type calcium channel subunit beta-3 / Voltage-dependent L-type calcium channel subunit alpha-1C
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsChen, Z. / Mondal, A. / Minor, D.L.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL080050 United States
National Institutes of Health/National Institute on Deafness and Other Communication Disorders (NIH/NIDCD)DC007664 United States
CitationJournal: Nat Struct Mol Biol / Year: 2023
Title: Structural basis for Caαδ:gabapentin binding.
Authors: Zhou Chen / Abhisek Mondal / Daniel L Minor /
Abstract: Gabapentinoid drugs for pain and anxiety act on the Caαδ-1 and Caαδ-2 subunits of high-voltage-activated calcium channels (Ca1s and Ca2s). Here we present the cryo-EM structure of the gabapentin- ...Gabapentinoid drugs for pain and anxiety act on the Caαδ-1 and Caαδ-2 subunits of high-voltage-activated calcium channels (Ca1s and Ca2s). Here we present the cryo-EM structure of the gabapentin-bound brain and cardiac Ca1.2/Caβ/Caαδ-1 channel. The data reveal a binding pocket in the Caαδ-1 dCache1 domain that completely encapsulates gabapentin and define Caαδ isoform sequence variations that explain the gabapentin binding selectivity of Caαδ-1 and Caαδ-2.
History
DepositionDec 2, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 22, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 12, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Jul 5, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)370,95222
Polymers366,0543
Non-polymers4,89819
Water543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: mass spectrometry
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 1 types, 1 molecules D

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


Mass: 125082.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: CACNA2D1, CACNL2A, CCHL2A / Production host: Homo sapiens (human) / References: UniProt: P13806

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

#2: 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: 187082.188 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: 53889.152 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: CACNB3, CACNLB3 / Production host: Homo sapiens (human) / References: UniProt: P54286

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Sugars , 2 types, 9 molecules

#4: 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.: 1
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
#5: 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.: 8
Source method: isolated from a genetically manipulated source
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 , 7 types, 13 molecules

#6: Chemical ChemComp-GBN / [1-(AMINOMETHYL)CYCLOHEXYL]ACETIC ACID / GABAPENTIN


Mass: 171.237 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H17NO2 / Comment: medication*YM
#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#8: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#9: Chemical ChemComp-WO9 / (2R)-3-{[(R)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-2-(dodecanoyloxy)propyl heptadecanoate


Mass: 649.879 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H68NO8P
#10: Chemical ChemComp-YSW / (2S)-3-{[(R)-(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-2-(dodecanoyloxy)propyl dodecanoate


Mass: 579.746 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H58NO8P
#11: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#12: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN
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

Component
IDNameTypeEntity IDParent-IDSource
1Ternary complex of human CaV alpha1C with rabbit CaV alpha2delta-1 and rabbit CaV beta3CELL#1-#30RECOMBINANT
2Human CaV alpha1CCOMPLEX#21RECOMBINANT
3Rabbit CaV alpha2delta-1COMPLEX#11RECOMBINANT
4Rabbit CaV beta3COMPLEX#31RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
11
220.187 MDaYES
330.125 MDaYES
440.1 MDaYES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Oryctolagus cuniculus (rabbit)9986
54Oryctolagus cuniculus (rabbit)9986
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
Buffer solutionpH: 8
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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 magnification: 105000 X / Nominal defocus max: 1700 nm / Nominal defocus min: 900 nm / Cs: 2.7 mm
Image recordingElectron dose: 46 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 259107 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00220132
ELECTRON MICROSCOPYf_angle_d0.46827298
ELECTRON MICROSCOPYf_dihedral_angle_d11.3257326
ELECTRON MICROSCOPYf_chiral_restr0.0393116
ELECTRON MICROSCOPYf_plane_restr0.0043429

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