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- PDB-7wlj: CryoEM structure of human low-voltage activated T-type calcium ch... -

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Basic information

Entry
Database: PDB / ID: 7wlj
TitleCryoEM structure of human low-voltage activated T-type calcium channel Cav3.3 in complex with mibefradil (MIB)
ComponentsVoltage-dependent T-type calcium channel subunit alpha-1I
KeywordsMEMBRANE PROTEIN / MIB
Function / homology
Function and homology information


sleep / high voltage-gated calcium channel activity / NCAM1 interactions / voltage-gated calcium channel complex / calcium ion import across plasma membrane / neuronal action potential / voltage-gated calcium channel activity / Smooth Muscle Contraction / signal transduction / plasma membrane
Similarity search - Function
Voltage-dependent calcium channel, T-type, alpha-1 subunit / Voltage-dependent calcium channel, alpha-1 subunit / Voltage-gated cation channel calcium and sodium / Voltage-dependent channel domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
1,2-Distearoyl-sn-glycerophosphoethanolamine / Chem-MWV / CHOLESTEROL HEMISUCCINATE / Voltage-dependent T-type calcium channel subunit alpha-1I
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsHe, L. / Yu, Z. / Dong, Y. / Chen, Q. / Zhao, Y.
Funding support China, 1items
OrganizationGrant numberCountry
Chinese Academy of Sciences China
CitationJournal: Nat Commun / Year: 2022
Title: Structure, gating, and pharmacology of human Ca3.3 channel.
Authors: Lingli He / Zhuoya Yu / Ze Geng / Zhuo Huang / Changjiang Zhang / Yanli Dong / Yiwei Gao / Yuhang Wang / Qihao Chen / Le Sun / Xinyue Ma / Bo Huang / Xiaoqun Wang / Yan Zhao /
Abstract: The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been ...The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type Ca3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. Ca3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type Ca channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the Ca3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.
History
DepositionJan 13, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 4, 2022Provider: repository / Type: Initial release
Revision 1.1May 25, 2022Group: 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.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Voltage-dependent T-type calcium channel subunit alpha-1I
hetero molecules


Theoretical massNumber of molelcules
Total (without water)253,01216
Polymers245,3731
Non-polymers7,63915
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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Protein / Sugars , 2 types, 3 molecules A

#1: Protein Voltage-dependent T-type calcium channel subunit alpha-1I / Voltage-gated calcium channel subunit alpha Cav3.3 / Ca(v)3.3


Mass: 245373.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CACNA1I, KIAA1120 / Production host: Homo sapiens (human) / References: UniProt: Q9P0X4
#6: 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.: 2 / 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, 13 molecules

#2: Chemical ChemComp-MWV / (1S,2S)-2-(2-{[3-(1H-benzimidazol-2-yl)propyl](methyl)amino}ethyl)-6-fluoro-1-(propan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate / Mibefradil


Mass: 495.629 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H38FN3O3 / Feature type: SUBJECT OF INVESTIGATION / Comment: channel blocker*YM
#3: 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.: 5 / Source method: obtained synthetically / Formula: C41H82NO8P / Comment: phospholipid*YM
#4: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#5: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C31H50O4

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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 / Cs: 2.7 mm
Image recordingElectron dose: 9.6 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 151492 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0049669
ELECTRON MICROSCOPYf_angle_d0.89113119
ELECTRON MICROSCOPYf_dihedral_angle_d12.0211370
ELECTRON MICROSCOPYf_chiral_restr0.0621537
ELECTRON MICROSCOPYf_plane_restr0.0041580

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