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- PDB-7jpk: Rabbit Cav1.1 in the presence of 100 micromolar (S)-(-)-Bay K8644... -

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Basic information

Entry
Database: PDB / ID: 7jpk
TitleRabbit Cav1.1 in the presence of 100 micromolar (S)-(-)-Bay K8644 in nanodiscs at 3.0 Angstrom resolution
Components
  • (Voltage-dependent 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


high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / positive regulation of muscle contraction / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / cellular response to caffeine / calcium ion import across plasma membrane / regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated calcium channel activity / release of sequestered calcium ion into cytosol / T-tubule ...high voltage-gated calcium channel activity / L-type voltage-gated calcium channel complex / positive regulation of muscle contraction / regulation of calcium ion transmembrane transport via high voltage-gated calcium channel / cellular response to caffeine / calcium ion import across plasma membrane / regulation of ryanodine-sensitive calcium-release channel activity / voltage-gated calcium channel activity / release of sequestered calcium ion into cytosol / T-tubule / muscle contraction / calcium channel regulator activity / sarcolemma / calcium ion transmembrane transport / transmembrane transporter binding / calmodulin binding / metal ion binding / plasma membrane
Similarity search - Function
von Willebrand factor type A domain / Voltage-dependent calcium channel, gamma-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1S subunit / PMP-22/EMP/MP20/Claudin tight junction / 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 ...von Willebrand factor type A domain / Voltage-dependent calcium channel, gamma-1 subunit / Voltage-dependent calcium channel, L-type, alpha-1S subunit / PMP-22/EMP/MP20/Claudin tight junction / 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-gated potassium channels. Chain C / 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 / : / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / von Willebrand factor type A domain / Helix Hairpins - #70 / VWFA domain profile. / von Willebrand factor (vWF) type A domain / Voltage-dependent channel domain superfamily / von Willebrand factor, type A / von Willebrand factor A-like domain superfamily / Four Helix Bundle (Hemerythrin (Met), subunit A) / Ion transport domain / Ion transport protein / Helix Hairpins / Up-down Bundle / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
1,2-Distearoyl-sn-glycerophosphoethanolamine / Chem-C8U / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOCHOLINE / 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
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 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: 2021
Title: Structural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Ca 1.1 by Dihydropyridine Compounds*.
Authors: Shuai Gao / Nieng Yan /
Abstract: 1,4-Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L-type voltage-gated Ca (Ca ) 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 (Ca ) channels. DHP compounds exhibit chirality-specific antagonistic or agonistic effects. The structure of rabbit Ca 1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remained elusive. Herein, we report five cryo-EM structures of nanodisc-embedded Ca 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.
History
DepositionAug 9, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Nov 18, 2020Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Dec 23, 2020Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.name
Revision 1.2Mar 10, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.3Oct 16, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / em_admin / entity / pdbx_entity_nonpoly / pdbx_entry_details / pdbx_modification_feature
Item: _chem_comp.name / _chem_comp.pdbx_synonyms ..._chem_comp.name / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_entry_details.has_protein_modification
Revision 1.4May 28, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 28, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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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)370,32515
Polymers362,4063
Non-polymers7,91912
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area18990 Å2
ΔGint-166 kcal/mol
Surface area102870 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 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


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


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


Mass: 790.145 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C44H88NO8P / Comment: phospholipid*YM
#7: Chemical ChemComp-C8U / methyl (4~{S})-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-1,4-dihydropyridine-3-carboxylate


Mass: 356.297 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H15F3N2O4 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: rCav1.1-100S / 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: rCav1.1-100S 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 FIELD
Image recordingElectron dose: 53 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
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 87516 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00518589
ELECTRON MICROSCOPYf_angle_d0.6425220
ELECTRON MICROSCOPYf_dihedral_angle_d9.09712900
ELECTRON MICROSCOPYf_chiral_restr0.0452839
ELECTRON MICROSCOPYf_plane_restr0.0053184

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