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- PDB-7jpw: Rabbit Cav1.1 in the presence of 100 micromolar (R)-(+)-Bay K8644... -

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Basic information

Entry
Database: PDB / ID: 7jpw
TitleRabbit Cav1.1 in the presence of 100 micromolar (R)-(+)-Bay K8644 in nanodiscs at 3.2 Angstrom resolution
Components
  • (Voltage-dependent calcium channel ...Voltage-gated calcium channel) x 2
  • Voltage-dependent L-type calcium channel subunit alpha-1S
KeywordsTRANSPORT PROTEIN / rCav1.1 / Channels / Calcium Ion-Selective / drugs
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 / calcium channel regulator activity / cellular response to caffeine / voltage-gated ion channel activity / voltage-gated calcium channel activity / regulation of ion transmembrane transport / calcium ion transmembrane transport / regulation of ryanodine-sensitive calcium-release channel activity ...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 / calcium channel regulator activity / cellular response to caffeine / voltage-gated ion channel activity / voltage-gated calcium channel activity / regulation of ion transmembrane transport / calcium ion transmembrane transport / regulation of ryanodine-sensitive calcium-release channel activity / calcium channel activity / T-tubule / sarcolemma / ion channel binding / calmodulin binding / integral component of plasma membrane / metal ion binding
von Willebrand factor, type A / VWA N-terminal / Voltage-dependent calcium channel, alpha-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1S subunit / Ion transport domain / Voltage-dependent calcium channel, gamma-1 subunit / Voltage-dependent calcium channel, gamma subunit / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain ...von Willebrand factor, type A / VWA N-terminal / Voltage-dependent calcium channel, alpha-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1S subunit / Ion transport domain / Voltage-dependent calcium channel, gamma-1 subunit / Voltage-dependent calcium channel, gamma subunit / Voltage-dependent calcium channel, alpha-2/delta subunit, conserved region / Voltage-dependent calcium channel, alpha-1 subunit, IQ domain / Voltage-dependent channel domain superfamily / Voltage-dependent L-type calcium channel, IQ-associated domain / Voltage-gated calcium channel subunit alpha, C-terminal / von Willebrand factor A-like domain superfamily / PMP-22/EMP/MP20/Claudin superfamily
Voltage-dependent L-type calcium channel subunit alpha-1S / Voltage-dependent calcium channel subunit alpha-2/delta-1 / Voltage-dependent calcium channel gamma-1 subunit
Biological speciesOryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYan, N. / Gao, S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)DMR-1420541 United States
CitationJournal: Angew Chem Int Ed Engl / Year: 2020
Title: Structural Basis of Cav1.1 Modulation by Dihydropyridine Compounds.
Authors: Nieng Yan / Shuai Gao /
Abstract: 1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca 2+ (Ca v ) channels. DHP compounds exhibit chirality-specific antagonistic or ...1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca 2+ (Ca v ) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. The structure of rabbit Ca v 1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remains elusive. Here, we report five cryo-EM structures of nanodisc-embedded Ca v 1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist ( R )-(+)-Bay K8644, and a titration of its agonistic enantiomer ( S )-(-)-Bay K8644 at resolutions of 2.9-3.4 Å. The amlodipine-bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that ( S )-(-)-Bay K8644, when acting as an agonist, is insufficient to lock the activated state of the channel for a prolonged duration.
Validation Report
SummaryFull reportAbout validation report
History
DepositionAug 10, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release

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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
F: Voltage-dependent calcium channel subunit alpha-2/delta-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)370,32615
Polymers362,4063
Non-polymers7,92012
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18410 Å2
ΔGint-170 kcal/mol
Surface area103130 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: 212240.594 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
#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: 125082.906 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Oryctolagus cuniculus (rabbit) / References: UniProt: P13806

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Non-polymers , 4 types, 12 molecules

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


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


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


Mass: 790.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#7: Chemical ChemComp-VFY / methyl (4~{R})-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate


Mass: 357.304 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H16F3N2O4 / Feature type: SUBJECT OF INVESTIGATION

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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: rCav1.1-100R / Type: COMPLEX / Entity ID: #1-#3 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Buffer solutionpH: 8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: rCav1.1-100R was in lipid nanodisc
Specimen supportDetails: unspecified
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K / Details: blot for 5 seconds before plunging

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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: 50 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.17rc2_3619: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 94695 / Symmetry type: POINT
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01418589
ELECTRON MICROSCOPYf_angle_d0.89925220
ELECTRON MICROSCOPYf_dihedral_angle_d9.21612901
ELECTRON MICROSCOPYf_chiral_restr0.0572839
ELECTRON MICROSCOPYf_plane_restr0.0063184

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