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- PDB-7yg5: Structure of human R-type voltage-gated CaV2.3-alpha2/delta1-beta... -

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Basic information

Entry
Database: PDB / ID: 7yg5
TitleStructure of human R-type voltage-gated CaV2.3-alpha2/delta1-beta1 channel complex in the topiramate-bound state
Components(Voltage-dependent ...) x 3
KeywordsMEMBRANE PROTEIN / Voltage-gated calcium channel / CaV2.3 / Complex
Function / homology
Function and homology information


regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / calcium ion transmembrane transport via high voltage-gated calcium channel / Phase 2 - plateau phase / high voltage-gated calcium channel activity / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / positive regulation of muscle contraction / NCAM1 interactions / regulation of ventricular cardiac muscle cell membrane repolarization ...regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / calcium ion transmembrane transport via high voltage-gated calcium channel / Phase 2 - plateau phase / high voltage-gated calcium channel activity / membrane depolarization during bundle of His cell action potential / L-type voltage-gated calcium channel complex / positive regulation of muscle contraction / NCAM1 interactions / regulation of ventricular cardiac muscle cell membrane repolarization / cardiac muscle cell action potential involved in contraction / calcium ion transport into cytosol / voltage-gated monoatomic cation channel activity / 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 / regulation of heart rate by cardiac conduction / calcium ion import across plasma membrane / regulation of calcium ion transport / neuronal dense core vesicle / voltage-gated calcium channel activity / presynaptic active zone membrane / T-tubule / sarcoplasmic reticulum / calcium channel regulator activity / Regulation of insulin secretion / GABA-ergic synapse / calcium ion transmembrane transport / cellular response to amyloid-beta / calcium ion transport / chemical synaptic transmission / neuronal cell body / calcium ion binding / synapse / extracellular exosome / metal ion binding / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, R-type, alpha-1 subunit / Voltage-dependent calcium channel, L-type, beta-1 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 / 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, R-type, alpha-1 subunit / Voltage-dependent calcium channel, L-type, beta-1 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 / 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 / EF-hand calcium-binding domain profile. / EF-hand domain / Ion transport domain / Ion transport protein / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
1,2-Distearoyl-sn-glycerophosphoethanolamine / HEXADECANE / Chem-TOR / CHOLESTEROL HEMISUCCINATE / Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent L-type calcium channel subunit beta-1 / Voltage-dependent R-type calcium channel subunit alpha-1E
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsGao, Y. / Zhao, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Biochem Biophys Res Commun / Year: 2024
Title: Structural insights into the allosteric effects of the antiepileptic drug topiramate on the Ca2.3 channel.
Authors: Yiwei Gao / Qinru Bai / Xuejun Cai Zhang / Yan Zhao /
Abstract: The R-type voltage-gated calcium channel Ca2.3 is predominantly located in the presynapse and is implicated in distinct types of epileptic seizures. It has consequently emerged as a molecular target ...The R-type voltage-gated calcium channel Ca2.3 is predominantly located in the presynapse and is implicated in distinct types of epileptic seizures. It has consequently emerged as a molecular target in seizure treatment. Here, we determined the cryo-EM structure of the Ca2.3-α2δ1-β1 complex in the topiramate-bound state at a 3.0 Å resolution. We provide a snapshot of the binding site of topiramate, a widely prescribed antiepileptic drug, on a voltage-gated ion channel. The binding site is located at an intracellular juxtamembrane hydrophilic cavity. Further structural analysis revealed that topiramate may allosterically facilitate channel inactivation. These findings provide fundamental insights into the mechanism underlying the inhibitory effect of topiramate on Ca and Na channels, elucidating a previously unseen modulator binding site and thus pointing toward a route for the development of new drugs.
History
DepositionJul 11, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 29, 2023Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update
Revision 1.2Nov 13, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)463,73234
Polymers452,5483
Non-polymers11,18431
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Voltage-dependent ... , 3 types, 3 molecules ABD

#1: Protein Voltage-dependent R-type calcium channel subunit alpha-1E / Brain calcium channel II / BII / Calcium channel / L type / alpha-1 polypeptide / isoform 6 / ...Brain calcium channel II / BII / Calcium channel / L type / alpha-1 polypeptide / isoform 6 / Voltage-gated calcium channel subunit alpha Cav2.3


Mass: 262055.984 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA1E, CACH6, CACNL1A6 / Production host: Homo sapiens (human) / References: UniProt: Q15878
#2: Protein Voltage-dependent L-type calcium channel subunit beta-1 / CAB1 / Calcium channel voltage-dependent subunit beta 1


Mass: 65799.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNB1, CACNLB1 / Production host: Homo sapiens (human) / References: UniProt: Q02641
#3: 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 , 3 types, 11 molecules

#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#5: Polysaccharide beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-3DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b3-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(3+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#11: 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 , 5 types, 20 molecules

#6: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C31H50O4
#7: Chemical
ChemComp-R16 / HEXADECANE


Mass: 226.441 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C16H34
#8: 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
#9: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: Ca
#10: Chemical ChemComp-TOR / [(3aS,5aR,8aR,8bS)-2,2,7,7-tetramethyltetrahydro-3aH-bis[1,3]dioxolo[4,5-b:4',5'-d]pyran-3a-yl]methyl sulfamate / topiramate


Mass: 339.362 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H21NO8S / Feature type: SUBJECT OF INVESTIGATION

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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: Human R-type voltage-gated calcium channel CaV2.3-alpha2/delta1-beta1 complex in the topiramate-bound state
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK 293-F
Buffer solutionpH: 7.5
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Details: This sample was obtained from the monodispersed peak fractions of the size-exclusion chromatography.
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 273 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: 135000 X / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm / Cs: 2.7 mm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 6.7 sec. / Electron dose: 60 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2097
Image scansSampling size: 0.52 µm / Width: 7676 / Height: 7420 / Movie frames/image: 32 / Used frames/image: 1-32

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Processing

EM software
IDNameVersionCategory
2SerialEM3.6image acquisition
4Gctf1.06CTF correction
7UCSF Chimera1.15model fitting
9Coot0.9.6.2-premodel refinement
10cryoSPARC3.3.1initial Euler assignment
11cryoSPARC3.3.1final Euler assignment
12RELION3.1classification
13cryoSPARC3.3.13D reconstruction
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 787518
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 68522 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT
Atomic model buildingPDB-ID: 7VFS

7vfs


Accession code: 7VFS / Source name: PDB / Type: experimental model

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