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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/homologyTransient 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 / Transient receptor potential channel / regulation of urine volume / calcium ion homeostasis / calcium channel activity / Ion transport domain / calcium ion transport / Ion transport protein ...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 / Transient receptor potential channel / regulation of urine volume / calcium ion homeostasis / calcium channel activity / Ion transport domain / calcium ion transport / Ion transport protein / Ankyrin repeat profile. / Ankyrin repeat / Ankyrin repeat region circular profile. / Ankyrin repeat-containing domain / Ankyrin repeat-containing domain superfamily / Ankyrin repeats (3 copies) / protein tetramerization / apical plasma membrane / calmodulin binding / integral component of plasma membrane / metal ion binding / Transient receptor potential cation channel subfamily V member 5
Function and homology information
Specimen sourceOryctolagus cuniculus / mammal / European rabbit /
MethodElectron microscopy (4.8 Å resolution / Particle / Single particle) / Transmission electron microscopy
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. / Filizola, M. / Rohacs, T. / Han, S. / Moiseenkova-Bell, V.Y.
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 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.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Sep 29, 2017 / Release: Dec 27, 2017
RevisionDateData content typeGroupCategoryItemProviderType
1.0Dec 27, 2017Structure modelrepositoryInitial release
1.1Jan 17, 2018Structure modelAuthor supporting evidencepdbx_audit_support_pdbx_audit_support.funding_organization
1.2Jan 31, 2018Structure modelDatabase referencescitation / citation_author_citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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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
Polyers331,5994
Non-polymers1,5675
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551
Buried area (Å2)21520
ΔGint (kcal/M)-217
Surface area (Å2)131990

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Components

#1: Protein/peptide
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: (gene. exp.) Oryctolagus cuniculus / mammal / European rabbit /
Gene: Trpv5, Ecac1 / Production host: Saccharomyces cerevisiae / 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 / Formula: C18H15Cl3N2O
#3: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Formula: Ca / : Calcium

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / Reconstruction method: SINGLE PARTICLE

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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
Source (recombinant)Organism: Saccharomyces cerevisiae / Strain: BJ5457
Buffer solutionpH: 8
Buffer component
IDConc.UnitsNameFormulaBuffer ID
1150mMSodium ChlorideNaCl1
220mMHEPESC8H18N2O4S1
30.064mMDMNGC43H80O221
42mMTCEPC9H15O6P1
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 kelvins

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyMicroscope model: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 45455 / 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) / Number 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
10RELION2.0INITIAL EULER ASSIGNMENT
11RELION2.0FINAL EULER ASSIGNMENT
13RELION2.0RECONSTRUCTION
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNumber of particles selected: 925927
SymmetryPoint symmetry: C4
3D reconstructionResolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 50566 / Symmetry type: POINT
Atomic model buildingRef protocol: OTHER / Ref 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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