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- EMDB-60798: Cryo-EM structure of human TRPV4 intracellular domain in complex ... -

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Entry
Database: EMDB / ID: EMD-60798
TitleCryo-EM structure of human TRPV4 intracellular domain in complex with GTPase RhoA
Map data
Sample
  • Complex: Cryo-EM structure of human TRPV4 intracellular domain in complex with GTPase RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4
    • Protein or peptide: Transforming protein RhoA
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsComplex / MEMBRANE PROTEIN / Hydrolase
Function / homology
Function and homology information


stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / regulation of response to osmotic stress / osmosensor activity / vasopressin secretion / positive regulation of striated muscle contraction / calcium ion import into cytosol / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / positive regulation of macrophage inflammatory protein 1 alpha production ...stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / regulation of response to osmotic stress / osmosensor activity / vasopressin secretion / positive regulation of striated muscle contraction / calcium ion import into cytosol / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / positive regulation of macrophage inflammatory protein 1 alpha production / hyperosmotic salinity response / 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 / alpha-beta T cell lineage commitment / aortic valve formation / mitotic cleavage furrow formation / positive regulation of lipase activity / bone trabecula morphogenesis / 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 / negative regulation of intracellular steroid hormone receptor signaling pathway / Axonal growth inhibition (RHOA activation) / Axonal growth stimulation / cellular hypotonic salinity response / cleavage furrow formation / regulation of neural precursor cell proliferation / cellular hypotonic response / cortical microtubule organization / regulation of modification of postsynaptic actin cytoskeleton / regulation of osteoblast proliferation / forebrain radial glial cell differentiation / multicellular organismal-level water homeostasis / regulation of modification of postsynaptic structure / apical junction assembly / cell junction assembly / negative regulation of cell migration involved in sprouting angiogenesis / cellular response to chemokine / establishment of epithelial cell apical/basal polarity / positive regulation of vascular permeability / beta selection / regulation of systemic arterial blood pressure by endothelin / osmosensory signaling pathway / negative regulation of oxidative phosphorylation / negative regulation of motor neuron apoptotic process / RHO GTPases Activate ROCKs / negative regulation of cell size / RHO GTPases activate CIT / cell-cell junction assembly / Sema4D induced cell migration and growth-cone collapse / PCP/CE pathway / cellular response to osmotic stress / positive regulation of monocyte chemotactic protein-1 production / RHO GTPases activate KTN1 / calcium ion import / cell volume homeostasis / positive regulation of podosome assembly / apolipoprotein A-I-mediated signaling pathway / positive regulation of alpha-beta T cell differentiation / Sema4D mediated inhibition of cell attachment and migration / wound healing, spreading of cells / positive regulation of leukocyte adhesion to vascular endothelial cell / PI3K/AKT activation / Wnt signaling pathway, planar cell polarity pathway / motor neuron apoptotic process / odontogenesis / ossification involved in bone maturation / regulation of aerobic respiration / regulation of focal adhesion assembly / TRP channels / negative chemotaxis / apical junction complex / cortical actin cytoskeleton / EPHA-mediated growth cone collapse / myosin binding / stress fiber assembly / positive regulation of cytokinesis / regulation of neuron projection development / diet induced thermogenesis / positive regulation of macrophage chemotaxis / RHOC GTPase cycle / cellular response to cytokine stimulus / cerebral cortex cell migration / ERBB2 Regulates Cell Motility / microtubule polymerization / cleavage furrow / semaphorin-plexin signaling pathway / calcium ion import across plasma membrane / androgen receptor signaling pathway / ficolin-1-rich granule membrane / RHOA GTPase cycle / mitotic spindle assembly / negative regulation of cell-substrate adhesion / alpha-tubulin binding / Rho protein signal transduction
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 / Rab subfamily of small GTPases / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.16 Å
AuthorsYuan Z / Ruan SS / Li SL
Funding support China, 2 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82425104 China
National Natural Science Foundation of China (NSFC)82150208 China
CitationJournal: Circulation / Year: 2025
Title: Inactivation of RhoA for Hypertension Treatment Through the TRPV4-RhoA-RhoGDI1 Axis.
Authors: Jiawen Wang / Zhen Yuan / Na Yu / Qian Jiao / Honglei Zhou / Wenjie Liao / Jiwei Shan / Shanshan Ruan / Yi Zhao / Ya Mo / Luyao Qi / Tiejun Li / Jianjun Fu / Bowen Ke / Yufang Xu / Xuhong ...Authors: Jiawen Wang / Zhen Yuan / Na Yu / Qian Jiao / Honglei Zhou / Wenjie Liao / Jiwei Shan / Shanshan Ruan / Yi Zhao / Ya Mo / Luyao Qi / Tiejun Li / Jianjun Fu / Bowen Ke / Yufang Xu / Xuhong Qian / Jian Zhang / Zhenjiang Zhao / Shiliang Li / Rui Wang / Honglin Li
Abstract: BACKGROUND: The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the ...BACKGROUND: The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the RhoA signaling pathway are limited in hypertension treatment, suffering from poor efficacy, insufficient specificity, and developmental challenges.
METHODS: Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation. VSMC, hypertensive animal models, ...METHODS: Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation. VSMC, hypertensive animal models, and Myh11-CRE (smooth muscle-specific RhoGDI1 knockout) mice were used to investigate the role of the TRPV4 (transient receptor potential cation channel subfamily V member 4)-RhoA-RhoGDI1 (Rho GDP dissociation inhibitor 1) axis in hypertension.
RESULTS: AH001 ((R)-1-(3-ethylphenyl) ethane-1,2-diol) was identified as a novel inhibitor of the RhoA signaling pathway. It targets the TRPV4-RhoA-RhoGDI1 axis to effectively sequester inactive RhoA- ...RESULTS: AH001 ((R)-1-(3-ethylphenyl) ethane-1,2-diol) was identified as a novel inhibitor of the RhoA signaling pathway. It targets the TRPV4-RhoA-RhoGDI1 axis to effectively sequester inactive RhoA-GDP in the plasma membrane and cytoplasm, which is distinct from typical RhoA inhibition modes. The cryo-EM structure of the TRPV4-RhoA complex showed that AH001-bound TRPV4 adopts a closed state with RhoA in an inactive GDP-bound state. Functional studies further revealed that AH001 reduced the pool of active RhoA by enhancing TRPV4-RhoA binding and facilitating RhoGDI1-RhoA interaction in VSMC. This inhibition notably decreased both acute and long-term blood pressure and prevented vascular remodeling in Ang II-induced hypertensive mice and spontaneously hypertensive rats. However, these antihypertensive effects were weakened in and Myh11-CRE mice. Additionally, AH001 effectively inhibited VSMC contraction via the RhoA/ROCK (Rho-associated protein kinase)/MYPT1 (myosin phosphatase target subunit 1)/MLC (myosin light chain 2) signaling pathway and suppressed VSMC phenotype switching to myofibroblasts through the RhoA/ROCK/LIMK1 (LIM domain kinase)/cofilin/MRTF-A (myocardin-related transcription factor A)/SRF (serum response factor) signaling cascade. TRPV4 and RhoGDI1 knockdown attenuated AH001's inhibition of VSMC contraction and phenotypic switching to myofibroblasts.
CONCLUSIONS: This study revealed a novel mode of RhoA signaling inhibition targeting the TRPV4-RhoA-RhoGDI1 axis, offering new insights for future antihypertensive drug development and proposing ...CONCLUSIONS: This study revealed a novel mode of RhoA signaling inhibition targeting the TRPV4-RhoA-RhoGDI1 axis, offering new insights for future antihypertensive drug development and proposing innovative strategies for targeting challenging Rho GTPases.
History
DepositionJul 13, 2024-
Header (metadata) releaseMay 28, 2025-
Map releaseMay 28, 2025-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_60798.png

Downloads & links

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Map

FileDownload / File: emd_60798.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 320 pix.
= 345.6 Å		1.08 Å/pix.
x 320 pix.
= 345.6 Å		1.08 Å/pix.
x 320 pix.
= 345.6 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.72
Minimum - Maximum-3.7341025 - 5.629144
Average (Standard dev.)-0.0022576938 (±0.07585183)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 345.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_60798_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_60798_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of human TRPV4 intracellular domain in complex ...

EntireName: Cryo-EM structure of human TRPV4 intracellular domain in complex with GTPase RhoA
Components
  • Complex: Cryo-EM structure of human TRPV4 intracellular domain in complex with GTPase RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4
    • Protein or peptide: Transforming protein RhoA
  • Ligand: GUANOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Cryo-EM structure of human TRPV4 intracellular domain in complex ...

SupramoleculeName: Cryo-EM structure of human TRPV4 intracellular domain in complex with GTPase RhoA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transient receptor potential cation channel subfamily V member 4

MacromoleculeName: Transient receptor potential cation channel subfamily V member 4
type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 73.038719 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: VFNRPILFDI VSRGSTADLD GLLPFLLTHK KRLTDEEFRE PSTGKTCLPK ALLNLSNGRN DTIPVLLDIA ERTGNMREFI NSPFRDIYY RGQTALHIAI ERRCKHYVEL LVAQGADVHA QARGRFFQPK DEGGYFYFGE LPLSLAACTN QPHIVNYLTE N PHKKADMR ...String:
VFNRPILFDI VSRGSTADLD GLLPFLLTHK KRLTDEEFRE PSTGKTCLPK ALLNLSNGRN DTIPVLLDIA ERTGNMREFI NSPFRDIYY RGQTALHIAI ERRCKHYVEL LVAQGADVHA QARGRFFQPK DEGGYFYFGE LPLSLAACTN QPHIVNYLTE N PHKKADMR RQDSRGNTVL HALVAIADNT RENTKFVTKM YDLLLLKCAR LFPDSNLEAV LNNDGLSPLM MAAKTGKIGI FQ HIIRREV TDEDTRHLSR KFKDWAYGPV YSSLYDLSSL DTCGEEASVL EILVYNSKIE NRHEMLAVEP INELLRDKWR KFG AVSFYI NVVSYLCAMV IFTLTAYYQP LEGTPPYPYR TTVDYLRLAG EVITLFTGVL FFFTNIKDLF MKKCPGVNSL FIDG SFQLL YFIYSVLVIV SAALYLAGIE AYLAVMVFAL VLGWMNALYF TRGLKLTGTY SIMIQKILFK DLFRFLLVYL LFMIG YASA LVSLLNPCAN MKVCNEDQTN CTVPTYPSCR DSETFSTFLL DLFKLTIGMG DLEMLSSTKY PVVFIILLVT YIILTF VLL LNMLIALMGE TVGQVSKESK HIWKLQWATT ILDIERSFPV FLRKAFRSGE MVTVGKSSDG TPDRRWCFRV DEVNWSH

UniProtKB: Transient receptor potential cation channel subfamily V member 4

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Macromolecule #2: Transforming protein RhoA

MacromoleculeName: Transforming protein RhoA / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: small monomeric GTPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.799158 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAIRKKLVI VGDGACGKTC LLIVFSKDQF PEVYVPTVFE NYVADIEVDG KQVELALWDT AGQEDYDRLR PLSYPDTDVI LMCFSIDSP DSLENIPEKW TPEVKHFCPN VPIILVGNKK DLRNDEHTRR ELAKMKQEPV KPEEGRDMAN RIGAFGYMEC S AKTKDGVR ...String:
MAAIRKKLVI VGDGACGKTC LLIVFSKDQF PEVYVPTVFE NYVADIEVDG KQVELALWDT AGQEDYDRLR PLSYPDTDVI LMCFSIDSP DSLENIPEKW TPEVKHFCPN VPIILVGNKK DLRNDEHTRR ELAKMKQEPV KPEEGRDMAN RIGAFGYMEC S AKTKDGVR EVFEMATRAA LQARRGKKKS GCLVL

UniProtKB: Transforming protein RhoA

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Macromolecule #3: GUANOSINE-5'-DIPHOSPHATE

MacromoleculeName: GUANOSINE-5'-DIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 1 / Formula: GDP
Molecular weightTheoretical: 443.201 Da
Chemical component information

ChemComp-GDP:
GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying molecule*YM

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 1 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOCONTINUUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsCalibrated magnification: 64000 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.16 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 132000
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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