+
Open data
-
Basic information
Entry | Database: PDB / ID: 8ju6 | ||||||
---|---|---|---|---|---|---|---|
Title | Structure of human TRPV4 with antagonist GSK279 | ||||||
![]() | Transient receptor potential cation channel subfamily V member 4,3C-GFP | ||||||
![]() | MEMBRANE PROTEIN / Channel | ||||||
Function / homology | ![]() stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / 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 ...stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / 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 / regulation of response to osmotic stress / 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 / cellular hypotonic salinity response / multicellular organismal-level water homeostasis / osmosensory signaling pathway / positive regulation of vascular permeability / cellular response to osmotic stress / cell volume homeostasis / positive regulation of monocyte chemotactic protein-1 production / calcium ion import / cell-cell junction assembly / TRP channels / regulation of aerobic respiration / cortical actin cytoskeleton / positive regulation of macrophage chemotaxis / beta-tubulin binding / cytoplasmic microtubule / diet induced thermogenesis / microtubule polymerization / alpha-tubulin binding / monoatomic cation channel activity / response to mechanical stimulus / SH2 domain binding / filopodium / actin filament organization / adherens junction / protein kinase C binding / calcium ion transmembrane transport / positive regulation of JNK cascade / ruffle membrane / response to insulin / calcium channel activity / cilium / actin filament binding / intracellular calcium ion homeostasis / positive regulation of inflammatory response / positive regulation of interleukin-6 production / calcium ion transport / glucose homeostasis / negative regulation of neuron projection development / lamellipodium / actin binding / positive regulation of cytosolic calcium ion concentration / cellular response to heat / growth cone / actin cytoskeleton organization / microtubule binding / positive regulation of ERK1 and ERK2 cascade / calmodulin binding / response to hypoxia / apical plasma membrane / focal adhesion / lipid binding / protein kinase binding / negative regulation of transcription by RNA polymerase II / cell surface / endoplasmic reticulum / ATP binding / identical protein binding / membrane / metal ion binding / plasma membrane Similarity search - Function | ||||||
Biological species | ![]() synthetic construct (others) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.45 Å | ||||||
![]() | Fan, J. / Lei, X. | ||||||
Funding support | ![]()
| ||||||
![]() | ![]() Title: Structural Pharmacology of TRPV4 Antagonists. Authors: Junping Fan / Chang Guo / Daohong Liao / Han Ke / Jing Lei / Wenjun Xie / Yuliang Tang / Makoto Tominaga / Zhuo Huang / Xiaoguang Lei / ![]() ![]() Abstract: The nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many ...The nonselective calcium-permeable Transient Receptor Potential Cation Channel Subfamily V Member4 (TRPV4) channel regulates various physiological activities. Dysfunction of TRPV4 is linked to many severe diseases, including edema, pain, gastrointestinal disorders, lung diseases, and inherited neurodegeneration. Emerging TRPV4 antagonists show potential clinical benefits. However, the molecular mechanisms of TRPV4 antagonism remain poorly understood. Here, cryo-electron microscopy (cryo-EM) structures of human TRPV4 are presented in-complex with two potent antagonists, revealing the detailed binding pockets and regulatory mechanisms of TRPV4 gating. Both antagonists bind to the voltage-sensing-like domain (VSLD) and stabilize the channel in closed states. These two antagonists induce TRPV4 to undergo an apparent fourfold to twofold symmetry transition. Moreover, it is demonstrated that one of the antagonists binds to the VSLD extended pocket, which differs from the canonical VSLD pocket. Complemented with functional and molecular dynamics simulation results, this study provides crucial mechanistic insights into TRPV4 regulation by small-molecule antagonists, which may facilitate future drug discovery targeting TRPV4. | ||||||
History |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 466.9 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | 362.1 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
---|
-Related structure data
Related structure data | ![]() 36660MC ![]() 8ju5C ![]() 8jviC ![]() 8jvjC M: map data used to model this data C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
|
---|---|
1 |
|
-
Components
#1: Protein | Mass: 128628.547 Da / Num. of mol.: 4 Source method: isolated from a genetically manipulated source Details: Author stated: The section (872-874) is the cloning site. The domain (875-882) is PreScission Site. The domain (883-1116) is corresponding to this sfGFP (462-695 amino acids, GenBank: ...Details: Author stated: The section (872-874) is the cloning site. The domain (875-882) is PreScission Site. The domain (883-1116) is corresponding to this sfGFP (462-695 amino acids, GenBank: ALP48449.1). The domain (1117-1144) is the expression Tag. Source: (gene. exp.) ![]() Gene: TRPV4, VRL2, VROAC / Production host: ![]() #2: Chemical | ChemComp-XPW / Has ligand of interest | Y | |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-
Sample preparation
Component | Name: TRPV4 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
---|---|
Molecular weight | Value: 0.4 MDa / Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-
Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-
Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
3D reconstruction | Resolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 206979 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
|