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- PDB-8hmb: Cryo-EM structure of human high-voltage activated L-type calcium ... -

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Basic information

Entry
Database: PDB / ID: 8hmb
TitleCryo-EM structure of human high-voltage activated L-type calcium channel CaV1.2 in complex with benidipine (BEN)
Components
  • (Voltage-dependent ...) x 2
  • Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2
KeywordsMEMBRANE PROTEIN / ben bound state
Function / homology
Function and homology information


voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / 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 / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential ...voltage-gated calcium channel activity involved in regulation of presynaptic cytosolic calcium levels / positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / regulation of membrane repolarization during action potential / Presynaptic depolarization and calcium channel opening / 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 / membrane depolarization during AV node cell action potential / membrane depolarization during bundle of His cell action potential / photoreceptor ribbon synapse / L-type voltage-gated calcium channel complex / cardiac muscle cell action potential involved in contraction / positive regulation of calcium ion transport / NCAM1 interactions / regulation of ventricular cardiac muscle cell membrane repolarization / calcium ion import / Sensory processing of sound by inner hair cells of the cochlea / calcium ion transport into cytosol / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / neuromuscular junction development / voltage-gated calcium channel complex / neuronal dense core vesicle / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / calcium ion import across plasma membrane / regulation of calcium ion transport / voltage-gated calcium channel activity / T-tubule / visual perception / sarcoplasmic reticulum / Regulation of insulin secretion / protein localization to plasma membrane / postsynaptic density membrane / calcium channel activity / Adrenaline,noradrenaline inhibits insulin secretion / cellular response to amyloid-beta / calcium ion transport / actin filament binding / presynapse / perikaryon / chemical synaptic transmission / dendrite / extracellular exosome / metal ion binding / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, L-type, beta-2 subunit / CACNB2, SH3 domain / Voltage-dependent calcium channel, L-type, alpha-1C 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 / 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-2 subunit / CACNB2, SH3 domain / Voltage-dependent calcium channel, L-type, alpha-1C 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 / 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 / Src homology 3 domains / 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 / : / HEXADECANE / Voltage-dependent L-type calcium channel subunit alpha / Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent L-type calcium channel subunit beta-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsWei, Y. / Yu, Z. / Zhao, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nat Commun / Year: 2024
Title: Structural bases of inhibitory mechanism of Ca1.2 channel inhibitors.
Authors: Yiqing Wei / Zhuoya Yu / Lili Wang / Xiaojing Li / Na Li / Qinru Bai / Yuhang Wang / Renjie Li / Yufei Meng / Hao Xu / Xianping Wang / Yanli Dong / Zhuo Huang / Xuejun Cai Zhang / Yan Zhao /
Abstract: The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved ...The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6, S6, and S6 helices and forms extensive hydrophobic interactions with Ca1.2. Our structure elucidates that benidipine is located in the D-D fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5, S6, and S6 helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.
History
DepositionDec 2, 2022Deposition site: PDBJ / Processing site: RCSB
Revision 1.0Apr 24, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2
D: Voltage-dependent L-type calcium channel subunit alpha
E: Voltage-dependent calcium channel subunit alpha-2/delta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)442,50925
Polymers436,0973
Non-polymers6,41222
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 ... , 2 types, 2 molecules DE

#2: Protein Voltage-dependent L-type calcium channel subunit alpha


Mass: 243947.016 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA1C / Production host: Homo sapiens (human) / References: UniProt: A0A0A0MSA1
#3: Protein Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-gated calcium channel / Voltage-gated calcium channel subunit alpha-2/delta-1


Mass: 121197.406 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 / Sugars , 2 types, 9 molecules C

#1: Protein Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2 / CAB2 / Calcium channel voltage-dependent subunit beta 2 / Lambert-Eaton myasthenic syndrome antigen B / MYSB


Mass: 70952.688 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNB2, CACNLB2, MYSB / Production host: Homo sapiens (human) / References: UniProt: Q08289
#8: 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: 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, 14 molecules

#4: Chemical
ChemComp-R16 / HEXADECANE / Hexadecane


Mass: 226.441 Da / Num. of mol.: 8
Source method: isolated from a genetically manipulated source
Formula: C16H34
#5: 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.: 3
Source method: isolated from a genetically manipulated source
Formula: C41H82NO8P / Comment: phospholipid*YM
#6: Chemical ChemComp-A1AC8 / (3R)-1-benzylpiperidin-3-yl methyl (2R,3R,4R,5R,6S)-2,6-dimethyl-4-(3-nitrophenyl)piperidine-3,5-dicarboxylate


Mass: 506.570 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H32N3O6 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca

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Details

Has ligand of interestY

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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: CaV3.3 / Type: COMPLEX / Entity ID: #1 / 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 FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 9.6 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 65662 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00719874
ELECTRON MICROSCOPYf_angle_d0.76726883
ELECTRON MICROSCOPYf_dihedral_angle_d15.4552869
ELECTRON MICROSCOPYf_chiral_restr0.0513096
ELECTRON MICROSCOPYf_plane_restr0.0043325

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