[English] 日本語
Yorodumi
- PDB-8jvj: Structure of human TRPV4 with antagonist A2 and RhoA -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 8jvj
TitleStructure of human TRPV4 with antagonist A2 and RhoA
Components
  • Transforming protein RhoA
  • Transient receptor potential cation channel subfamily V member 4,3C-GFP
KeywordsMEMBRANE PROTEIN / Channel
Function / homology
Function and homology information


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 / 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 / aortic valve formation / alpha-beta T cell lineage commitment / mitotic cleavage furrow formation / bone trabecula morphogenesis / positive regulation of lipase activity / endothelial tube lumen extension / skeletal muscle satellite cell migration / positive regulation of vascular associated smooth muscle contraction / angiotensin-mediated vasoconstriction involved in regulation of systemic arterial blood pressure / SLIT2:ROBO1 increases RHOA activity / RHO GTPases Activate Rhotekin and Rhophilins / Roundabout signaling pathway / cellular hypotonic response / negative regulation of intracellular steroid hormone receptor signaling pathway / regulation of response to osmotic stress / Axonal growth inhibition (RHOA activation) / Axonal growth stimulation / regulation of neural precursor cell proliferation / cleavage furrow formation / cellular hypotonic salinity response / osmosensory signaling pathway / regulation of modification of postsynaptic actin cytoskeleton / multicellular organismal-level water homeostasis / regulation of osteoblast proliferation / forebrain radial glial cell differentiation / cell junction assembly / apical junction assembly / regulation of systemic arterial blood pressure by endothelin / cellular response to chemokine / negative regulation of cell migration involved in sprouting angiogenesis / beta selection / establishment of epithelial cell apical/basal polarity / regulation of modification of postsynaptic structure / positive regulation of vascular permeability / negative regulation of cell size / RHO GTPases Activate ROCKs / negative regulation of oxidative phosphorylation / negative regulation of motor neuron apoptotic process / cellular response to osmotic stress / RHO GTPases activate CIT / calcium ion import / PCP/CE pathway / Sema4D induced cell migration and growth-cone collapse / RHO GTPases activate KTN1 / cell volume homeostasis / positive regulation of monocyte chemotactic protein-1 production / apolipoprotein A-I-mediated signaling pathway / positive regulation of podosome assembly / cell-cell junction assembly / negative regulation of cell-substrate adhesion / TRP channels / Wnt signaling pathway, planar cell polarity pathway / Sema4D mediated inhibition of cell attachment and migration / ossification involved in bone maturation / positive regulation of alpha-beta T cell differentiation / odontogenesis / motor neuron apoptotic process / PI3K/AKT activation / wound healing, spreading of cells / positive regulation of leukocyte adhesion to vascular endothelial cell / apical junction complex / regulation of focal adhesion assembly / negative chemotaxis / regulation of aerobic respiration / cortical actin cytoskeleton / positive regulation of macrophage chemotaxis / myosin binding / EPHA-mediated growth cone collapse / stress fiber assembly / beta-tubulin binding / regulation of neuron projection development / RHOC GTPase cycle / diet induced thermogenesis / cytoplasmic microtubule / androgen receptor signaling pathway / positive regulation of cytokinesis / microtubule polymerization / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / cellular response to cytokine stimulus / cleavage furrow / semaphorin-plexin signaling pathway / calcium ion import across plasma membrane / Rho protein signal transduction / ficolin-1-rich granule membrane / alpha-tubulin binding
Similarity search - Function
Transient receptor potential cation channel subfamily V member 4 / Small GTPase Rho / small GTPase Rho family profile. / Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family ...Transient receptor potential cation channel subfamily V member 4 / Small GTPase Rho / small GTPase Rho family profile. / Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein / Small GTP-binding protein domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / Transforming protein RhoA / Transient receptor potential cation channel subfamily V member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.44 Å
AuthorsFan, J. / Lei, X.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21625201 China
CitationJournal: Adv Sci (Weinh) / Year: 2024
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
DepositionJun 28, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 8, 2024Provider: repository / Type: Initial release

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily V member 4,3C-GFP
B: Transient receptor potential cation channel subfamily V member 4,3C-GFP
C: Transient receptor potential cation channel subfamily V member 4,3C-GFP
D: Transient receptor potential cation channel subfamily V member 4,3C-GFP
E: Transforming protein RhoA
F: Transforming protein RhoA
G: Transforming protein RhoA
H: Transforming protein RhoA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)604,00112
Polymers601,7118
Non-polymers2,2914
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

-
Components

#1: Protein
Transient receptor potential cation channel subfamily V member 4,3C-GFP / TrpV4 / Osm-9-like TRP channel 4 / OTRPC4 / Transient receptor potential protein 12 / TRP12 / ...TrpV4 / Osm-9-like TRP channel 4 / OTRPC4 / Transient receptor potential protein 12 / TRP12 / Vanilloid receptor-like channel 2 / Vanilloid receptor-like protein 2 / VRL-2 / Vanilloid receptor-related osmotically-activated channel / VR-OAC


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.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: TRPV4, VRL2, VROAC / Production host: Homo sapiens (human) / References: UniProt: Q9HBA0
#2: Protein
Transforming protein RhoA / / Rho cDNA clone 12 / h12


Mass: 21799.158 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RHOA, ARH12, ARHA, RHO12 / Production host: Homo sapiens (human) / References: UniProt: P61586, small monomeric GTPase
#3: Chemical
ChemComp-F9M / [6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]pyridin-3-yl]-[(1~{S},5~{R})-3-[5-(trifluoromethyl)pyrimidin-2-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone


Mass: 572.628 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C25H23F3N8OS2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

-
Sample preparation

ComponentName: Complex of TRPV4 and RhoA / Type: COMPLEX / Entity ID: #2, #1 / Source: RECOMBINANT
Molecular weightValue: 0.4 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

-
Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

-
Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 47803 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01326534
ELECTRON MICROSCOPYf_angle_d1.90235975
ELECTRON MICROSCOPYf_dihedral_angle_d15.639778
ELECTRON MICROSCOPYf_chiral_restr0.1434063
ELECTRON MICROSCOPYf_plane_restr0.0234531

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more