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- PDB-6b5v: Structure of TRPV5 in complex with econazole -

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Basic information

Entry
Database: PDB / ID: 6b5v
TitleStructure of TRPV5 in complex with econazole
ComponentsTransient receptor potential cation channel subfamily V member 5
KeywordsMEMBRANE PROTEIN / TRPV5 / Econazole / Transient Receptor Potential Channel / Cryo-EM
Function / homology
Function and homology information


regulation of urine volume / calcium ion import across plasma membrane / calcium ion homeostasis / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / protein homotetramerization / calmodulin binding / apical plasma membrane / identical protein binding ...regulation of urine volume / calcium ion import across plasma membrane / calcium ion homeostasis / calcium ion transmembrane transport / calcium channel activity / calcium ion transport / protein homotetramerization / calmodulin binding / apical plasma membrane / identical protein binding / metal ion binding / plasma membrane
Similarity search - Function
Transient receptor potential cation channel subfamily V member 5 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily ...Transient receptor potential cation channel subfamily V member 5 / Transient receptor potential cation channel subfamily V member 5/6 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Chem-ECL / Transient receptor potential cation channel subfamily V member 5
Similarity search - Component
Biological speciesOryctolagus cuniculus (rabbit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.8 Å
AuthorsHughes, T.E.T. / Lodowski, D.T. / Huynh, K.W. / Yazici, A. / del Rosario, J. / Kapoor, A. / Basak, S. / Samanta, A. / Chakrapani, S. / Zhou, Z.H. ...Hughes, T.E.T. / Lodowski, D.T. / Huynh, K.W. / Yazici, A. / del Rosario, J. / Kapoor, A. / Basak, S. / Samanta, A. / Chakrapani, S. / Zhou, Z.H. / Filizola, M. / Rohacs, T. / Han, S. / Moiseenkova-Bell, V.Y.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)NIGMS 1R01GM103899-01A1 United States
CitationJournal: Nat Struct Mol Biol / Year: 2018
Title: Structural basis of TRPV5 channel inhibition by econazole revealed by cryo-EM.
Authors: Taylor E T Hughes / David T Lodowski / Kevin W Huynh / Aysenur Yazici / John Del Rosario / Abhijeet Kapoor / Sandip Basak / Amrita Samanta / Xu Han / Sudha Chakrapani / Z Hong Zhou / Marta ...Authors: Taylor E T Hughes / David T Lodowski / Kevin W Huynh / Aysenur Yazici / John Del Rosario / Abhijeet Kapoor / Sandip Basak / Amrita Samanta / Xu Han / Sudha Chakrapani / Z Hong Zhou / Marta Filizola / Tibor Rohacs / Seungil Han / Vera Y Moiseenkova-Bell /
Abstract: The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca, that is present primarily at the ...The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca reabsorption. Here we present the structure of the full-length rabbit TRPV5 channel as determined using cryo-EM in complex with its inhibitor econazole. This structure reveals that econazole resides in a hydrophobic pocket analogous to that occupied by phosphatidylinositides and vanilloids in TRPV1, thus suggesting conserved mechanisms for ligand recognition and lipid binding among TRPV channels. The econazole-bound TRPV5 structure adopts a closed conformation with a distinct lower gate that occludes Ca permeation through the channel. Structural comparisons between TRPV5 and other TRPV channels, complemented with molecular dynamics (MD) simulations of the econazole-bound TRPV5 structure, allowed us to gain mechanistic insight into TRPV5 channel inhibition by small molecules.
History
DepositionSep 29, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release
Revision 1.1Jan 17, 2018Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Jan 31, 2018Group: Database references / Category: citation / citation_author
Item: _citation.journal_abbrev / _citation.journal_volume ..._citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Mar 13, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 5
B: Transient receptor potential cation channel subfamily V member 5
D: Transient receptor potential cation channel subfamily V member 5
C: Transient receptor potential cation channel subfamily V member 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)333,1659
Polymers331,5994
Non-polymers1,5675
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area21520 Å2
ΔGint-217 kcal/mol
Surface area131990 Å2

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Components

#1: Protein
Transient receptor potential cation channel subfamily V member 5 / TrpV5 / Epithelial calcium channel 1 / ECaC1 / Osm-9-like TRP channel 3 / OTRPC3


Mass: 82899.656 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Oryctolagus cuniculus (rabbit) / Gene: Trpv5, Ecac1 / Production host: Saccharomyces cerevisiae (brewer's yeast) / Strain (production host): BJ5457 / References: UniProt: Q9XSM3
#2: Chemical
ChemComp-ECL / 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole / R-Econazole


Mass: 381.684 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C18H15Cl3N2O
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca

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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: Full-length TRPV5 in complex with econazole / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Oryctolagus cuniculus (rabbit)
Source (recombinant)Organism: Saccharomyces cerevisiae (brewer's yeast) / Strain: BJ5457
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMSodium ChlorideNaClSodium chloride1
220 mMHEPESC8H18N2O4S1
30.064 mMDMNGC43H80O221
42 mMTCEPC9H15O6P1
SpecimenConc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 magnification: 45455 X / Cs: 2.7 mm
Image recordingAverage exposure time: 0.2 sec. / Electron dose: 2 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Num. of real images: 3313
Image scansMovie frames/image: 50

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Processing

SoftwareName: PHENIX / Version: dev_2870: / Classification: refinement
EM software
IDNameVersionCategory
2Leginon0.1image acquisition
4Gctf1.06CTF correction
7Coot0.8.8-premodel fitting
9PHENIX1.12rc0model refinement
10RELION2initial Euler assignment
11RELION2final Euler assignment
13RELION23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 925927
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 50566 / Symmetry type: POINT
Atomic model buildingProtocol: OTHER / Space: REAL / Target criteria: correlation coefficient
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00319612
ELECTRON MICROSCOPYf_angle_d0.81226652
ELECTRON MICROSCOPYf_dihedral_angle_d12.83811560
ELECTRON MICROSCOPYf_chiral_restr0.0422992
ELECTRON MICROSCOPYf_plane_restr0.0043324

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