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- PDB-8t1e: Closed-state cryo-EM structure of full-length human TRPV4 in the ... -
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Open data
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Basic information
Entry | Database: PDB / ID: 8t1e | |||||||||||||||||||||
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Title | Closed-state cryo-EM structure of full-length human TRPV4 in the presence of 4a-PDD | |||||||||||||||||||||
![]() | Transient receptor potential cation channel subfamily V member 4,Enhanced green fluorescent protein | |||||||||||||||||||||
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Function / homology | ![]() blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / positive regulation of striated muscle contraction / calcium ion import into cytosol / positive regulation of macrophage inflammatory protein 1 alpha production / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response ...blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / positive regulation of striated muscle contraction / calcium ion import into cytosol / positive regulation of macrophage inflammatory protein 1 alpha production / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response / cortical microtubule organization / positive regulation of chemokine (C-X-C motif) ligand 1 production / positive regulation of chemokine (C-C motif) ligand 5 production / cartilage development involved in endochondral bone morphogenesis / cellular hypotonic response / regulation of response to osmotic stress / cellular hypotonic salinity response / multicellular organismal-level water homeostasis / osmosensory signaling pathway / positive regulation of vascular permeability / cellular response to osmotic stress / calcium ion import / cell volume homeostasis / positive regulation of monocyte chemotactic protein-1 production / cell-cell junction assembly / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||||||||||||||
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![]() | Talyzina, I.A. / Nadezhdin, K.D. / Neuberger, A. / Sobolevsky, A.I. | |||||||||||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Structure of human TRPV4 in complex with GTPase RhoA. Authors: Kirill D Nadezhdin / Irina A Talyzina / Aravind Parthasarathy / Arthur Neuberger / David X Zhang / Alexander I Sobolevsky / ![]() Abstract: Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in ...Transient receptor potential (TRP) channel TRPV4 is a polymodal cellular sensor that responds to moderate heat, cell swelling, shear stress, and small-molecule ligands. It is involved in thermogenesis, regulation of vascular tone, bone homeostasis, renal and pulmonary functions. TRPV4 is implicated in neuromuscular and skeletal disorders, pulmonary edema, and cancers, and represents an important drug target. The cytoskeletal remodeling GTPase RhoA has been shown to suppress TRPV4 activity. Here, we present a structure of the human TRPV4-RhoA complex that shows RhoA interaction with the membrane-facing surface of the TRPV4 ankyrin repeat domains. The contact interface reveals residues that are mutated in neuropathies, providing an insight into the disease pathogenesis. We also identify the binding sites of the TRPV4 agonist 4α-PDD and the inhibitor HC-067047 at the base of the S1-S4 bundle, and show that agonist binding leads to pore opening, while channel inhibition involves a π-to-α transition in the pore-forming helix S6. Our structures elucidate the interaction interface between hTRPV4 and RhoA, as well as residues at this interface that are involved in TRPV4 disease-causing mutations. They shed light on TRPV4 activation and inhibition and provide a template for the design of future therapeutics for treatment of TRPV4-related diseases. | |||||||||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 513.6 KB | Display | ![]() |
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PDB format | ![]() | 412.7 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 40961MC ![]() 8t1bC ![]() 8t1cC ![]() 8t1dC ![]() 8t1fC C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 127717.938 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() Gene: TRPV4, VRL2, VROAC, egfp / Cell line (production host): HEK293S / Production host: ![]() ![]() #2: Chemical | ChemComp-9ZR / [( #3: Chemical | ChemComp-YJ0 / ( #4: Chemical | #5: Water | ChemComp-HOH / | ![]() Has ligand of interest | N | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: ![]() |
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Sample preparation
Component | Name: full-length human TRPV4 in the presence of 4a-PDD / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT | ||||||||||||||||||||||||||||||
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Molecular weight | Value: 0.51 MDa / Experimental value: NO | ||||||||||||||||||||||||||||||
Source (natural) | Organism: ![]() ![]() | ||||||||||||||||||||||||||||||
Source (recombinant) | Organism: ![]() ![]() ![]() | ||||||||||||||||||||||||||||||
Buffer solution | pH: 8 | ||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 3.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() | ||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3 | ||||||||||||||||||||||||||||||
Vitrification![]() | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: TFS KRIOS |
Electron gun | Electron source![]() ![]() |
Electron lens | Mode: BRIGHT FIELD![]() ![]() |
Image recording | Average exposure time: 2.4 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 15624 |
Image scans | Width: 11520 / Height: 8184 |
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Processing
EM software | Name: PHENIX / Version: 1.11.1_2575: / Category: model refinement | ||||||||||||||||||||||||
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CTF correction![]() | Type: NONE | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 3935964 | ||||||||||||||||||||||||
3D reconstruction![]() | Resolution: 2.77 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 75146 / Symmetry type: POINT | ||||||||||||||||||||||||
Atomic model building | Space: REAL | ||||||||||||||||||||||||
Refine LS restraints |
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