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

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Basic information

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


positive regulation of muscle contraction / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / voltage-gated monoatomic cation channel activity ...positive regulation of muscle contraction / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / positive regulation of high voltage-gated calcium channel activity / Phase 2 - plateau phase / calcium ion transmembrane transport via high voltage-gated calcium channel / membrane depolarization during bundle of His cell action potential / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / voltage-gated monoatomic cation channel activity / cardiac muscle cell action potential involved in contraction / NCAM1 interactions / regulation of ventricular cardiac muscle cell membrane repolarization / 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 / neuronal dense core vesicle / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / regulation of calcium ion transport / calcium ion import across plasma membrane / voltage-gated calcium channel activity / sarcoplasmic reticulum / Regulation of insulin secretion / calcium ion transmembrane transport / cellular response to amyloid-beta / calcium ion transport / chemical synaptic transmission / neuronal cell body / synapse / calcium ion binding / 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 L-type calcium channel subunit beta-1-4, N-terminal A domain / Voltage-dependent calcium channel, L-type, beta subunit / 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-dependent calcium channel, R-type, alpha-1 subunit / Voltage-dependent calcium channel, L-type, beta-1 subunit / Voltage-dependent L-type calcium channel subunit beta-1-4, N-terminal A domain / Voltage-dependent calcium channel, L-type, beta subunit / 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 / 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 / EF-hand calcium-binding domain profile. / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / 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 / 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: 3.1 Å
AuthorsGao, Y. / Qiu, Y. / Wei, Y. / Dong, Y. / Zhang, X.C. / Zhao, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37030304 China
CitationJournal: Nat Commun / Year: 2023
Title: Molecular insights into the gating mechanisms of voltage-gated calcium channel Ca2.3.
Authors: Yiwei Gao / Shuai Xu / Xiaoli Cui / Hao Xu / Yunlong Qiu / Yiqing Wei / Yanli Dong / Boling Zhu / Chao Peng / Shiqi Liu / Xuejun Cai Zhang / Jianyuan Sun / Zhuo Huang / Yan Zhao /
Abstract: High-voltage-activated R-type Ca2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we ...High-voltage-activated R-type Ca2.3 channel plays pivotal roles in many physiological activities and is implicated in epilepsy, convulsions, and other neurodevelopmental impairments. Here, we determine the high-resolution cryo-electron microscopy (cryo-EM) structure of human Ca2.3 in complex with the α2δ1 and β1 subunits. The VSD is stabilized in the resting state. Electrophysiological experiments elucidate that the VSD is not required for channel activation, whereas the other VSDs are essential for channel opening. The intracellular gate is blocked by the W-helix. A pre-W-helix adjacent to the W-helix can significantly regulate closed-state inactivation (CSI) by modulating the association and dissociation of the W-helix with the gate. Electrostatic interactions formed between the negatively charged domain on S6, which is exclusively conserved in the Ca2 family, and nearby regions at the alpha-interacting domain (AID) and S4-S5 helix are identified. Further functional analyses indicate that these interactions are critical for the open-state inactivation (OSI) of Ca2 channels.
History
DepositionApr 22, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 8, 2023Provider: repository / Type: Initial release

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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
D: Voltage-dependent calcium channel subunit alpha-2/delta-1
B: Voltage-dependent L-type calcium channel subunit beta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)458,75330
Polymers449,8903
Non-polymers8,86327
Water0
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 ADB

#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 / Cell line (production host): HEK 293-F / Production host: Homo sapiens (human) / References: UniProt: Q15878
#2: Protein Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-gated calcium channel / Voltage-gated calcium channel subunit alpha-2/delta-1


Mass: 122034.352 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA2D1, CACNL2A, CCHL2A, MHS3 / Cell line (production host): HEK 293-F / Production host: Homo sapiens (human) / References: UniProt: P54289
#3: 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 / Cell line (production host): HEK 293-F / Production host: Homo sapiens (human) / References: UniProt: Q02641

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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
#10: 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 / N-Acetylglucosamine


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 , 4 types, 16 molecules

#6: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Formula: C31H50O4
#7: Chemical
ChemComp-R16 / HEXADECANE / Hexadecane


Mass: 226.441 Da / Num. of mol.: 7
Source method: isolated from a genetically manipulated source
Formula: C16H34
#8: Chemical ChemComp-3PE / 1,2-Distearoyl-sn-glycerophosphoethanolamine / 3-SN-PHOSPHATIDYLETHANOLAMINE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / Phosphatidylethanolamine


Mass: 748.065 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
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

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Details

Has ligand of interestN

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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
Type: COMPLEX / Entity ID: #1, #3, #2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK 293-T
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.
Specimen supportGrid material: COPPER / 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 FIELDBright-field microscopy / Nominal magnification: 130000 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 scansWidth: 7676 / Height: 7420 / Movie frames/image: 32 / Used frames/image: 1-32

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.3.1particle selection
2SerialEM3.6image acquisition
4Gctf1.06CTF correction
7UCSF Chimera1.15model fitting
9cryoSPARC3.3.1initial Euler assignment
10cryoSPARC3.3.1final Euler assignment
11RELION3.1classification
12cryoSPARC3.3.13D reconstruction
13Coot0.9.6.2-premodel refinement
CTF correctionType: PHASE FLIPPING ONLY
Particle selectionNum. of particles selected: 787518
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 257473 / 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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