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- PDB-8jvj: Structure of human TRPV4 with antagonist A2 and RhoA -

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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 / calcium ion import into cytosol / regulation of response to osmotic stress / positive regulation of microtubule depolymerization / positive regulation of macrophage inflammatory protein 1 alpha production / hyperosmotic salinity response / positive regulation of striated muscle contraction ...stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / calcium ion import into cytosol / regulation of response to osmotic stress / positive regulation of microtubule depolymerization / positive regulation of macrophage inflammatory protein 1 alpha production / hyperosmotic salinity response / positive regulation of striated muscle contraction / cartilage development involved in endochondral bone morphogenesis / positive regulation of chemokine (C-X-C motif) ligand 1 production / positive regulation of chemokine (C-C motif) ligand 5 production / alpha-beta T cell lineage commitment / aortic valve formation / 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 / bone trabecula morphogenesis / RHO GTPases Activate Rhotekin and Rhophilins / Roundabout signaling pathway / negative regulation of intracellular steroid hormone receptor signaling pathway / cellular hypotonic salinity response / Axonal growth inhibition (RHOA activation) / Axonal growth stimulation / cleavage furrow formation / cellular hypotonic response / regulation of neural precursor cell proliferation / cortical microtubule organization / regulation of osteoblast proliferation / regulation of modification of postsynaptic actin cytoskeleton / multicellular organismal-level water homeostasis / forebrain radial glial cell differentiation / mitotic cleavage furrow formation / apical junction assembly / negative regulation of cell migration involved in sprouting angiogenesis / positive regulation of vascular permeability / beta selection / cell junction assembly / establishment of epithelial cell apical/basal polarity / cellular response to chemokine / negative regulation of motor neuron apoptotic process / regulation of systemic arterial blood pressure by endothelin / calcium ion import / negative regulation of oxidative phosphorylation / regulation of modification of postsynaptic structure / RHO GTPases Activate ROCKs / RHO GTPases activate CIT / negative regulation of cell size / negative regulation of brown fat cell differentiation / Sema4D induced cell migration and growth-cone collapse / osmosensory signaling pathway / PCP/CE pathway / cell-cell junction assembly / positive regulation of monocyte chemotactic protein-1 production / RHO GTPases activate KTN1 / positive regulation of alpha-beta T cell differentiation / positive regulation of podosome assembly / cell volume homeostasis / cellular response to osmotic stress / apolipoprotein A-I-mediated signaling pathway / wound healing, spreading of cells / Sema4D mediated inhibition of cell attachment and migration / motor neuron apoptotic process / positive regulation of leukocyte adhesion to vascular endothelial cell / odontogenesis / Wnt signaling pathway, planar cell polarity pathway / PI3K/AKT activation / ossification involved in bone maturation / regulation of focal adhesion assembly / androgen receptor signaling pathway / negative chemotaxis / EPHA-mediated growth cone collapse / regulation of aerobic respiration / cortical actin cytoskeleton / apical junction complex / stress fiber assembly / myosin binding / diet induced thermogenesis / TRP channels / positive regulation of cytokinesis / RHOC GTPase cycle / regulation of neuron projection development / positive regulation of macrophage chemotaxis / cellular response to cytokine stimulus / cerebral cortex cell migration / positive regulation of protein serine/threonine kinase activity / ERBB2 Regulates Cell Motility / cleavage furrow / semaphorin-plexin signaling pathway / microtubule polymerization / calcium ion import across plasma membrane / negative regulation of cell-substrate adhesion / ficolin-1-rich granule membrane / RHOA GTPase cycle / mitotic spindle assembly / positive regulation of T cell migration
Similarity search - Function
Transient receptor potential cation channel subfamily V member 4 / Small GTPase Rho / Small GTPase Rho domain 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 domain 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 / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Rab subfamily of small GTPases / 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
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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
Water00
1


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

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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
Has protein modificationN

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Experimental details

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Experiment

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

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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

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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 FIELD / 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)

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Processing

EM softwareName: PHENIX / Category: model refinement
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

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