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- PDB-7vfu: Human N-type voltage gated calcium channel CaV2.2-alpha2/delta1-b... -

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Basic information

Entry
Database: PDB / ID: 7vfu
TitleHuman N-type voltage gated calcium channel CaV2.2-alpha2/delta1-beta1 complex, bound to ziconotide
Components
  • (Voltage-dependent ...) x 3
  • Omega-conotoxin MVIIA
KeywordsMEMBRANE PROTEIN / Voltage gated calcium channel / N-type / complex
Function / homology
Function and homology information


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 / positive regulation of muscle contraction / membrane depolarization during bundle of His cell action potential / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / host cell presynaptic membrane ...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 / positive regulation of muscle contraction / membrane depolarization during bundle of His cell action potential / high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / host cell presynaptic membrane / 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 / ion channel inhibitor activity / neuromuscular junction development / calcium ion import across plasma membrane / Phase 0 - rapid depolarisation / neuronal dense core vesicle / regulation of heart rate by cardiac conduction / response to amyloid-beta / regulation of calcium ion transport / calcium channel regulator activity / voltage-gated calcium channel activity / T-tubule / sarcoplasmic reticulum / calcium ion transmembrane transport / modulation of chemical synaptic transmission / cellular response to amyloid-beta / calcium ion transport / amyloid-beta binding / toxin activity / chemical synaptic transmission / neuronal cell body / calcium ion binding / synapse / extracellular exosome / extracellular region / ATP binding / metal ion binding / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, N-type, alpha-1 subunit / Conotoxin, omega-type, conserved site / Omega-conotoxin family signature. / Voltage-dependent calcium channel, L-type, beta-1 subunit / Conotoxin / Conotoxin / 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, N-type, alpha-1 subunit / Conotoxin, omega-type, conserved site / Omega-conotoxin family signature. / Voltage-dependent calcium channel, L-type, beta-1 subunit / Conotoxin / Conotoxin / 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 / 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
Chem-PT5 / HEXADECANE / CHOLESTEROL HEMISUCCINATE / Omega-conotoxin MVIIA / Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent N-type calcium channel subunit alpha-1B / Voltage-dependent L-type calcium channel subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Conus magus (magus cone)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsDong, Y. / Gao, Y. / Wang, Y. / Zhao, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of SciencesXDB37030304 China
CitationJournal: Cell Rep / Year: 2021
Title: Closed-state inactivation and pore-blocker modulation mechanisms of human Ca2.2.
Authors: Yanli Dong / Yiwei Gao / Shuai Xu / Yuhang Wang / Zhuoya Yu / Yue Li / Bin Li / Tian Yuan / Bei Yang / Xuejun Cai Zhang / Daohua Jiang / Zhuo Huang / Yan Zhao /
Abstract: N-type voltage-gated calcium (Ca) channels mediate Ca influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and ...N-type voltage-gated calcium (Ca) channels mediate Ca influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human Ca2.2 complex in apo, ziconotide-bound, and two Ca2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP) molecule, which is distinct from the other three VSDs of Ca2.2, as well as activated VSDs observed in previous structures of Ca channels. This structure reveals the molecular basis for the unique inactivation process of Ca2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II-III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.
History
DepositionSep 13, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 3, 2021Provider: repository / Type: Initial release
Revision 1.1Feb 16, 2022Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID

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Structure visualization

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  • Deposited structure unit
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Assembly

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


Theoretical massNumber of molelcules
Total (without water)466,16939
Polymers455,9764
Non-polymers10,19335
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area22460 Å2
ΔGint-135 kcal/mol
Surface area108900 Å2

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Components

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

#1: Protein Voltage-dependent N-type calcium channel subunit alpha-1B / Brain calcium channel III / BIII / Calcium channel / L type / alpha-1 polypeptide isoform 5 / ...Brain calcium channel III / BIII / Calcium channel / L type / alpha-1 polypeptide isoform 5 / Voltage-gated calcium channel subunit alpha Cav2.2


Mass: 262831.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA1B, CACH5, CACNL1A5 / Production host: Homo sapiens (human) / References: UniProt: Q00975
#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 / Production host: Homo sapiens (human) / References: UniProt: Q02641
#4: 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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Protein/peptide , 1 types, 1 molecules E

#2: Protein/peptide Omega-conotoxin MVIIA / SNX-111


Mass: 2652.216 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Conus magus (magus cone) / References: UniProt: P05484

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Sugars , 3 types, 11 molecules

#5: 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
#6: 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: 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 , 4 types, 24 molecules

#7: Chemical
ChemComp-R16 / HEXADECANE


Mass: 226.441 Da / Num. of mol.: 18
Source method: isolated from a genetically manipulated source
Formula: C16H34
#8: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Formula: C31H50O4
#9: Chemical ChemComp-PT5 / [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate / Phosphatidylinositol 4,5-bisphosphate / PtdIns(4,5)P2


Mass: 1047.088 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C47H85O19P3 / Comment: phospholipid*YM
#10: 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: CaV2.2-alpha2delta1-beta1 complex / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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
Image recordingElectron dose: 9.6 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEM3.6image acquisition
4Gctf1.18CTF correction
10RELION3.1initial Euler assignment
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 203629 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00420383
ELECTRON MICROSCOPYf_angle_d0.59127517
ELECTRON MICROSCOPYf_dihedral_angle_d17.4152997
ELECTRON MICROSCOPYf_chiral_restr0.0433116
ELECTRON MICROSCOPYf_plane_restr0.0053425

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