|Entry||Database: PDB / ID: 6b5v|
|Title||Structure of TRPV5 in complex with econazole|
|Components||Transient receptor potential cation channel subfamily V member 5|
|Keywords||MEMBRANE PROTEIN / TRPV5 / Econazole / Transient Receptor Potential Channel / Cryo-EM|
|Function/homology||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 ...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 source||Oryctolagus cuniculus / mammal / European rabbit /|
|Method||Electron microscopy (4.8 Å resolution / Particle / Single particle) / Transmission electron microscopy|
|Authors||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.|
|Citation||Journal: 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.
SummaryFull reportAbout validation report
|Date||Deposition: Sep 29, 2017 / Release: Dec 27, 2017|
Downloads & links
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
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
|#3: Chemical|| ChemComp-CA / |
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / Reconstruction method: SINGLE PARTICLE|
|Component||Name: 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 solution||pH: 8|
|Specimen||Conc.: 2.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Specimen support||Grid type: Quantifoil R1.2/1.3|
|Vitrification||Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 kelvins|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Microscope model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELD / Nominal magnification: 45455 / Cs: 2.7 mm|
|Image recording||Average 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 scans||Movie frames/image: 50|
|Software||Name: PHENIX / Version: dev_2870: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Particle selection||Number of particles selected: 925927|
|Symmetry||Point symmetry: C4|
|3D reconstruction||Resolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number of particles: 50566 / Symmetry type: POINT|
|Atomic model building||Ref protocol: OTHER / Ref space: REAL / Target criteria: correlation coefficient|
|Refine LS restraints|
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