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- EMDB-22425: Rabbit Cav1.1 in the presence of 100 micromolar (R)-(+)-Bay K8644... -

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Basic information

Entry
Database: EMDB / ID: EMD-22425
TitleRabbit Cav1.1 in the presence of 100 micromolar (R)-(+)-Bay K8644 in nanodiscs at 3.2 Angstrom resolution
Map data
SamplerCav1.1-100R
  • Voltage-dependent L-type calcium channel subunit alpha-1S
  • (Voltage-dependent calcium channel ...Voltage-gated calcium channel) x 2
  • (ligand) x 4
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 / calcium 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 / calcium channel activity / regulation of ryanodine-sensitive calcium-release 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) / Rabbit (rabbit)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsYan N / Gao S
Funding support United States, 1 items
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 ReportPDB-ID: 7jpw

SummaryFull reportAbout validation report
History
DepositionAug 10, 2020-
Header (metadata) releaseNov 18, 2020-
Map releaseNov 18, 2020-
UpdateDec 2, 2020-
Current statusDec 2, 2020Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7jpw
  • Surface level: 0.02
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_22425.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.11 Å/pix.
x 280 pix.
= 311.92 Å
1.11 Å/pix.
x 280 pix.
= 311.92 Å
1.11 Å/pix.
x 280 pix.
= 311.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.114 Å
Density
Contour LevelBy AUTHOR: 0.02 / Movie #1: 0.02
Minimum - Maximum-0.08895473 - 0.1448058
Average (Standard dev.)-0.00000271200 (±0.0038986073)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 311.91998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1141.1141.114
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z311.920311.920311.920
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0890.145-0.000

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Supplemental data

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Sample components

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Entire rCav1.1-100R

EntireName: rCav1.1-100R / Number of components: 8

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Component #1: protein, rCav1.1-100R

ProteinName: rCav1.1-100R / Recombinant expression: No
SourceSpecies: Oryctolagus cuniculus (rabbit)

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Component #2: protein, Voltage-dependent L-type calcium channel subunit alpha-1S

ProteinName: Voltage-dependent L-type calcium channel subunit alpha-1S
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 212.240594 kDa
SourceSpecies: Rabbit (rabbit)

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Component #3: protein, Voltage-dependent calcium channel gamma-1 subunit

ProteinName: Voltage-dependent calcium channel gamma-1 subunit / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 25.082254 kDa
SourceSpecies: Rabbit (rabbit)

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Component #4: protein, Voltage-dependent calcium channel subunit alpha-2/delta-1

ProteinName: Voltage-dependent calcium channel subunit alpha-2/delta-1Voltage-gated calcium channel
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 125.082906 kDa
SourceSpecies: Rabbit (rabbit)

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Component #5: ligand, CALCIUM ION

LigandName: CALCIUM IONCalcium / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 4.007805 MDa

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Component #6: ligand, 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE

LigandName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE / Number of Copies: 9 / Recombinant expression: No
MassTheoretical: 0.748065 kDa

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Component #7: ligand, 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE

LigandName: 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.790145 kDa

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Component #8: ligand, methyl (4~{R})-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl...

LigandName: methyl (4~{R})-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.357304 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 5 mg/mL / pH: 8
Support filmunspecified
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 281 K / Humidity: 100 % / Details: blot for 5 seconds before plunging.

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 50 e/Å2 / Illumination mode: FLOOD BEAM
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 94695
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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