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- PDB-6jpa: Rabbit Cav1.1-Verapamil Complex -

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Basic information

Entry
Database: PDB / ID: 6jpa
TitleRabbit Cav1.1-Verapamil Complex
Components
  • (Voltage-dependent L-type calcium channel subunit beta- ...) x 2
  • (Voltage-dependent calcium channel ...Voltage-gated calcium channel) x 2
  • Voltage-dependent L-type calcium channel subunit alpha-1S
KeywordsMEMBRANE PROTEIN / Membrane protein complex modulated by FDA approved drug.
Function / homology
Function and homology information


L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / calcium ion import across plasma membrane / cellular response to caffeine / voltage-gated ion channel activity / calcium channel regulator activity / voltage-gated calcium channel activity / regulation of ion transmembrane transport / calcium channel activity / calcium ion transmembrane transport ...L-type voltage-gated calcium channel complex / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / calcium ion import across plasma membrane / cellular response to caffeine / voltage-gated ion channel activity / calcium channel regulator activity / voltage-gated calcium channel activity / regulation of ion transmembrane transport / calcium channel activity / calcium ion transmembrane transport / regulation of ryanodine-sensitive calcium-release channel activity / T-tubule / sarcolemma / ion channel binding / calmodulin binding / integral component of plasma membrane / go:0005623: / metal ion binding
Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / Voltage-dependent calcium channel, L-type, beta subunit / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain / Voltage-dependent L-type calcium channel, IQ-associated domain / VWA N-terminal / Voltage-dependent calcium channel, gamma subunit / Guanylate kinase/L-type calcium channel beta subunit / Ion transport domain / Voltage-dependent calcium channel, L-type, alpha-1S subunit / Voltage-dependent calcium channel, L-type, alpha-1 subunit ...Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / Voltage-dependent calcium channel, L-type, beta subunit / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain / Voltage-dependent L-type calcium channel, IQ-associated domain / VWA N-terminal / Voltage-dependent calcium channel, gamma subunit / Guanylate kinase/L-type calcium channel beta subunit / Ion transport domain / Voltage-dependent calcium channel, L-type, alpha-1S subunit / Voltage-dependent calcium channel, L-type, alpha-1 subunit / Voltage-dependent calcium channel, L-type, beta-1 subunit / Voltage-dependent calcium channel, gamma-1 subunit / PMP-22/EMP/MP20/Claudin superfamily / Voltage-dependent calcium channel, alpha-1 subunit / von Willebrand factor, type A / SH3 domain / Voltage-dependent channel domain superfamily / P-loop containing nucleoside triphosphate hydrolase / Guanylate kinase / Neuronal voltage-dependent calcium channel alpha 2acd / VWA N-terminal / von Willebrand factor type A domain / PMP-22/EMP/MP20/Claudin tight junction / Voltage gated calcium channel subunit beta domain 4Aa N terminal / Voltage-dependent L-type calcium channel, IQ-associated / Ion transport protein / von Willebrand factor A-like domain superfamily / SH3-like domain superfamily / Voltage-gated calcium channel subunit alpha, C-terminal / Butyryl-CoA Dehydrogenase, subunit A; domain 3 - #150 / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / SH3 Domains / SH3 type barrels. / P-loop containing nucleotide triphosphate hydrolases / Roll / Up-down Bundle / Rossmann fold / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Voltage-dependent L-type calcium channel subunit alpha-1S / Voltage-dependent calcium channel gamma-1 subunit / Voltage-dependent L-type calcium channel subunit beta-1 / Voltage-dependent calcium channel subunit alpha-2/delta-1
Biological speciesOryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsZhao, Y. / Huang, G. / Wu, J. / Yan, N.
Funding support China, 6items
OrganizationGrant numberCountry
Ministry of Science and Technology (China)2016YFA0500402 China
Ministry of Science and Technology (China)2015CB910101 China
National Natural Science Foundation of China31621092 China
National Natural Science Foundation of China31630017 China
National Institutes of Health/National Institute of General Medical SciencesR01GM130762 China
National Natural Science Foundation of China81861138009 China
CitationJournal: Cell / Year: 2019
Title: Molecular Basis for Ligand Modulation of a Mammalian Voltage-Gated Ca Channel.
Authors: Yanyu Zhao / Gaoxingyu Huang / Jianping Wu / Qiurong Wu / Shuai Gao / Zhen Yan / Jianlin Lei / Nieng Yan /
Abstract: The L-type voltage-gated Ca (Ca) channels are modulated by various compounds exemplified by 1,4-dihydropyridines (DHP), benzothiazepines (BTZ), and phenylalkylamines (PAA), many of which have been ...The L-type voltage-gated Ca (Ca) channels are modulated by various compounds exemplified by 1,4-dihydropyridines (DHP), benzothiazepines (BTZ), and phenylalkylamines (PAA), many of which have been used for characterizing channel properties and for treatment of hypertension and other disorders. Here, we report the cryoelectron microscopy (cryo-EM) structures of Ca1.1 in complex with archetypal antagonistic drugs, nifedipine, diltiazem, and verapamil, at resolutions of 2.9 Å, 3.0 Å, and 2.7 Å, respectively, and with a DHP agonist Bay K 8644 at 2.8 Å. Diltiazem and verapamil traverse the central cavity of the pore domain, directly blocking ion permeation. Although nifedipine and Bay K 8644 occupy the same fenestration site at the interface of repeats III and IV, the coordination details support previous functional observations that Bay K 8644 is less favored in the inactivated state. These structures elucidate the modes of action of different Ca ligands and establish a framework for structure-guided drug discovery.
Validation Report
SummaryFull reportAbout validation report
History
DepositionMar 26, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 12, 2019Provider: repository / Type: Initial release
Revision 1.1Oct 23, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._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
Revision 1.2Nov 6, 2019Group: Data collection / Other / Category: cell / Item: _cell.Z_PDB

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Structure visualization

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Assembly

Deposited unit
A: Voltage-dependent L-type calcium channel subunit alpha-1S
E: Voltage-dependent calcium channel gamma-1 subunit
B: Voltage-dependent L-type calcium channel subunit beta-1
C: Voltage-dependent L-type calcium channel subunit beta-1
F: Voltage-dependent calcium channel subunit alpha-2/delta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)438,05947
Polymers423,4115
Non-polymers14,64842
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, SDS-PAGE was supplemented
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TypeNameSymmetry operationNumber
identity operation1_5551
Buried area27480 Å2
ΔGint-127 kcal/mol
Surface area130360 Å2

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Voltage-dependent L-type calcium channel subunit alpha-1S / Calcium channel / L type / alpha-1 polypeptide / isoform 3 / skeletal muscle / Dihydropyridine ...Calcium channel / L type / alpha-1 polypeptide / isoform 3 / skeletal muscle / Dihydropyridine receptor alpha-1S subunit / DHPR / Voltage-gated calcium channel subunit alpha Cav1.1


Mass: 172146.531 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P07293

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Voltage-dependent calcium channel ... , 2 types, 2 molecules EF

#2: Protein Voltage-dependent calcium channel gamma-1 subunit / Dihydropyridine-sensitive L-type / skeletal muscle calcium channel subunit gamma


Mass: 25082.254 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P19518
#5: Protein Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-gated calcium channel / Voltage-gated calcium channel subunit alpha-2/delta-1


Mass: 118641.398 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P13806

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Voltage-dependent L-type calcium channel subunit beta- ... , 2 types, 2 molecules BC

#3: Protein Voltage-dependent L-type calcium channel subunit beta-1 / CAB1 / Calcium channel voltage-dependent subunit beta 1


Mass: 49642.430 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: CACNB1, CACNLB1 / Production host: Escherichia coli (E. coli) / References: UniProt: P19517
#4: Protein Voltage-dependent L-type calcium channel subunit beta-1 / CAB1 / Calcium channel voltage-dependent subunit beta 1


Mass: 57898.285 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P19517

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Sugars , 2 types, 25 molecules

#6: Sugar...
ChemComp-NAG / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Mass: 221.208 Da / Num. of mol.: 23
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
#13: Sugar ChemComp-BMA / BETA-D-MANNOSE / Mannose


Mass: 180.156 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Formula: C6H12O6

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Non-polymers , 6 types, 17 molecules

#7: Chemical ChemComp-CA / CALCIUM ION / Calcium


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca
#8: Chemical
ChemComp-3PE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / 3-SN-PHOSPHATIDYLETHANOLAMINE / Phosphatidylethanolamine


Mass: 748.065 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C41H82NO8P / Comment: phospholipid*YM
#9: Chemical ChemComp-PC1 / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 3-SN-PHOSPHATIDYLCHOLINE / Phosphatidylcholine


Mass: 790.145 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#10: Chemical ChemComp-9Z9 / (3beta,14beta,17beta,25R)-3-[4-methoxy-3-(methoxymethyl)butoxy]spirost-5-en


Mass: 544.805 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H56O5 / Comment: detergent*YM
#11: Chemical ChemComp-4YH / (2S)-2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile


Mass: 454.602 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H38N2O4
#12: Chemical ChemComp-ETA / ETHANOLAMINE / Ethanolamine


Mass: 61.083 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C2H7NO

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Details

Sequence detailsAs for the unusual connection between Y619-S621 of Chain F, the original amino acid for S620 is ...As for the unusual connection between Y619-S621 of Chain F, the original amino acid for S620 is Y620 and the density for this large side chain is missing from reconstruction. Authors suspect this to be a result of alternative splicing. The density in this beta strand, Y619 and S621, is very clear and allows accurate side chain assignment for this area and surrounding areas.

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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

Component
IDNameTypeEntity IDParent-IDSource
1Cav1.1-drug complexCOMPLEX2,3,4,50NATURAL
2Cav1.1-beta1a-alpha2-delta1-gamma complexCOMPLEX1, 2, 3, 4, 51NATURAL
Molecular weightUnits: KILODALTONS/NANOMETER / Experimental value: NO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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
Image recordingElectron dose: 48 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 QUANTUM (4k x 4k)
EM imaging opticsEnergyfilter name: GIF Quantum LS / Energyfilter slit width: 20 eV

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 433477 / Symmetry type: POINT

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