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- EMDB-7058: Structure of TRPV5 in complex with econazole -

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Basic information

Entry
Database: EMDB / ID: 7058
TitleStructure of TRPV5 in complex with econazole
Map dataTRPV5 in complex with econazole
SampleFull-length TRPV5 in complex with econazole
  • Transient receptor potential cation channel subfamily V member 5
  • (ligand) x 2
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
SourceOryctolagus cuniculus / European rabbit / mammal /
MethodCryo EM / single particle reconstruction / 4.8 Å resolution
AuthorsHughes TET / Lodowski DT
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 ReportPDB-ID: 6b5v

SummaryFull reportAbout validation report
DateDeposition: Sep 29, 2017 / Header (metadata) release: Nov 8, 2017 / Map release: Dec 27, 2017 / Last update: Jan 31, 2018

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF CHIMERA
  • Download
  • Surface view colored by cylindrical radius
  • Surface level: 0.04
  • Imaged by UCSF CHIMERA
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  • Surface view with fitted model
  • Atomic models: : PDB-6b5v
  • Surface level: 0.04
  • Imaged by UCSF CHIMERA
  • Download
3D viewer
Supplemental images

Downloads & links

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Map

Fileemd_7058.map.gz (map file in CCP4 format, 28312 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
192 pix
1.1 Å/pix.
= 211.2 Å
192 pix
1.1 Å/pix.
= 211.2 Å
192 pix
1.1 Å/pix.
= 211.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider package.

Voxel sizeX=Y=Z: 1.1 Å
Density
Contour Level:0.04 (by author), 0.04 (movie #1):
Minimum - Maximum-0.07627523 - 0.13983618
Average (Standard dev.)0.0016641174 (0.008344924)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions192192192
Origin-192-1920
Limit-1-1191
Spacing192192192
CellA=B=C: 211.20001 Å
α=β=γ: 90 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z211.200211.200211.200
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS-192-1920
NC/NR/NS192192192
D min/max/mean-0.0760.1400.002

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Supplemental data

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Sample components

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Entire Full-length TRPV5 in complex with econazole

EntireName: Full-length TRPV5 in complex with econazole / Number of components: 4

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Component #1: protein, Full-length TRPV5 in complex with econazole

ProteinName: Full-length TRPV5 in complex with econazole / Recombinant expression: No
SourceSpecies: Oryctolagus cuniculus / European rabbit / mammal /
Source (engineered)Expression System: Saccharomyces cerevisiae / / yeast / / Strain: BJ5457

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Component #2: protein, Transient receptor potential cation channel subfamily V ...

ProteinName: Transient receptor potential cation channel subfamily V member 5
Recombinant expression: No
MassTheoretical: 82.899656 kDa
Source (engineered)Expression System: Oryctolagus cuniculus / European rabbit / mammal /

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Component #3: ligand, 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)eth...

LigandName: 1-[(2R)-2-[(4-chlorobenzyl)oxy]-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole
Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 0.381684 kDa

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Component #4: ligand, CALCIUM ION

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

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: Cryo EM
Sample solutionSpecimen conc.: 2.5 mg/ml / pH: 8
VitrificationCryogen name: ETHANE / Temperature: 277 K / Humidity: 100 %

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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: 2 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 45455 X (nominal) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 (4k x 4k)

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Image acquisition

Image acquisitionNumber of digital images: 3313

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C4 (4 fold cyclic) / Number of projections: 50566
3D reconstructionSoftware: RELION / Resolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot (resolution assessment)

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Atomic model buiding

Output model

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