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- EMDB-36676: Structure of human TRPV4 with antagonist A2 and RhoA -

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Basic information

Entry
Database: EMDB / ID: EMD-36676
TitleStructure of human TRPV4 with antagonist A2 and RhoA
Map data
Sample
  • Complex: Complex of TRPV4 and RhoA
    • Protein or peptide: Transforming protein RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4,3C-GFP
  • Ligand: [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
KeywordsChannel / MEMBRANE PROTEIN
Function / homology
Function and homology information


stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / calcium ion import into cytosol / cartilage development involved in endochondral bone morphogenesis / positive regulation of microtubule depolymerization / positive regulation of macrophage inflammatory protein 1 alpha production / positive regulation of striated muscle contraction / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of chemokine (C-X-C motif) ligand 1 production ...stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / calcium ion import into cytosol / cartilage development involved in endochondral bone morphogenesis / positive regulation of microtubule depolymerization / positive regulation of macrophage inflammatory protein 1 alpha production / positive regulation of striated muscle contraction / positive regulation of chemokine (C-C motif) ligand 5 production / positive regulation of chemokine (C-X-C motif) ligand 1 production / alpha-beta T cell lineage commitment / aortic valve formation / beta selection / positive regulation of lipase activity / endothelial tube lumen extension / skeletal muscle satellite cell migration / bone trabecula morphogenesis / SLIT2:ROBO1 increases RHOA activity / RHO GTPases Activate Rhotekin and Rhophilins / Roundabout signaling pathway / cellular hypotonic salinity response / Axonal growth inhibition (RHOA activation) / Axonal growth stimulation / cleavage furrow formation / cellular hypotonic response / negative regulation of cell size / cortical microtubule organization / multicellular organismal-level water homeostasis / regulation of osteoblast proliferation / regulation of modification of postsynaptic actin cytoskeleton / diet induced thermogenesis / mitotic cleavage furrow formation / apical junction assembly / negative regulation of cell migration involved in sprouting angiogenesis / calcium ion import / establishment of epithelial cell apical/basal polarity / positive regulation of alpha-beta T cell differentiation / cell junction assembly / cellular response to chemokine / positive regulation of vascular permeability / negative regulation of oxidative phosphorylation / positive regulation of monocyte chemotactic protein-1 production / regulation of modification of postsynaptic structure / RHO GTPases Activate ROCKs / negative regulation of brown fat cell differentiation / RHO GTPases activate CIT / cell volume homeostasis / odontogenesis / PCP/CE pathway / cell-cell junction assembly / Sema4D induced cell migration and growth-cone collapse / RHO GTPases activate KTN1 / osmosensory signaling pathway / apolipoprotein A-I-mediated signaling pathway / cellular response to osmotic stress / wound healing, spreading of cells / Sema4D mediated inhibition of cell attachment and migration / positive regulation of leukocyte adhesion to vascular endothelial cell / Wnt signaling pathway, planar cell polarity pathway / PI3K/AKT activation / ossification involved in bone maturation / regulation of focal adhesion assembly / negative chemotaxis / regulation of aerobic respiration / EPHA-mediated growth cone collapse / cortical actin cytoskeleton / apical junction complex / stress fiber assembly / myosin binding / positive regulation of cytokinesis / RHOC GTPase cycle / positive regulation of macrophage chemotaxis / cellular response to cytokine stimulus / positive regulation of protein serine/threonine kinase activity / TRP channels / ERBB2 Regulates Cell Motility / cleavage furrow / microtubule polymerization / semaphorin-plexin signaling pathway / negative regulation of cell-substrate adhesion / calcium ion import across plasma membrane / mitotic spindle assembly / ficolin-1-rich granule membrane / RHOA GTPase cycle / response to mechanical stimulus / endothelial cell migration / positive regulation of T cell migration / alpha-tubulin binding / Rho protein signal transduction / beta-tubulin binding / positive regulation of stress fiber assembly / RHO GTPases activate PKNs / GPVI-mediated activation cascade / substrate adhesion-dependent cell spreading / cytoplasmic microtubule / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / monoatomic cation channel activity / negative regulation of reactive oxygen species biosynthetic process / cytoplasmic microtubule organization / positive regulation of neuron differentiation
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.44 Å
AuthorsFan J / Lei X
Funding support China, 1 items
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, 2023-
Header (metadata) releaseMay 8, 2024-
Map releaseMay 8, 2024-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36676.png

Downloads & links

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Map

FileDownload / File: emd_36676.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å		1.04 Å/pix.
x 256 pix.
= 266.24 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.04 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.28
Minimum - Maximum-1.5716672 - 2.5109248
Average (Standard dev.)-0.00066770177 (±0.07847149)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36676_half_map_1.map
Projections & Slices
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Histogram (log scale)

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Half map: #1

Fileemd_36676_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Complex of TRPV4 and RhoA

EntireName: Complex of TRPV4 and RhoA
Components
  • Complex: Complex of TRPV4 and RhoA
    • Protein or peptide: Transforming protein RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4,3C-GFP
  • Ligand: [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

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Supramolecule #1: Complex of TRPV4 and RhoA

SupramoleculeName: Complex of TRPV4 and RhoA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2, #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 400 KDa

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

MacromoleculeName: Transient receptor potential cation channel subfamily V member 4,3C-GFP
type: protein_or_peptide / ID: 1
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.
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 128.628547 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MADSSEGPRA GPGEVAELPG DESGTPGGEA FPLSSLANLF EGEDGSLSPS PADASRPAGP GDGRPNLRMK FQGAFRKGVP NPIDLLEST LYESSVVPGP KKAPMDSLFD YGTYRHHSSD NKRWRKKIIE KQPQSPKAPA PQPPPILKVF NRPILFDIVS R GSTADLDG ...String:
MADSSEGPRA GPGEVAELPG DESGTPGGEA FPLSSLANLF EGEDGSLSPS PADASRPAGP GDGRPNLRMK FQGAFRKGVP NPIDLLEST LYESSVVPGP KKAPMDSLFD YGTYRHHSSD NKRWRKKIIE KQPQSPKAPA PQPPPILKVF NRPILFDIVS R GSTADLDG LLPFLLTHKK RLTDEEFREP STGKTCLPKA LLNLSNGRND TIPVLLDIAE RTGNMREFIN SPFRDIYYRG QT ALHIAIE RRCKHYVELL VAQGADVHAQ ARGRFFQPKD EGGYFYFGEL PLSLAACTNQ PHIVNYLTEN PHKKADMRRQ DSR GNTVLH ALVAIADNTR ENTKFVTKMY DLLLLKCARL FPDSNLEAVL NNDGLSPLMM AAKTGKIGIF QHIIRREVTD EDTR HLSRK FKDWAYGPVY SSLYDLSSLD TCGEEASVLE ILVYNSKIEN RHEMLAVEPI NELLRDKWRK FGAVSFYINV VSYLC AMVI FTLTAYYQPL EGTPPYPYRT TVDYLRLAGE VITLFTGVLF FFTNIKDLFM KKCPGVNSLF IDGSFQLLYF IYSVLV IVS AALYLAGIEA YLAVMVFALV LGWMNALYFT RGLKLTGTYS IMIQKILFKD LFRFLLVYLL FMIGYASALV SLLNPCA NM KVCNEDQTNC TVPTYPSCRD SETFSTFLLD LFKLTIGMGD LEMLSSTKYP VVFIILLVTY IILTFVLLLN MLIALMGE T VGQVSKESKH IWKLQWATTI LDIERSFPVF LRKAFRSGEM VTVGKSSDGT PDRRWCFRVD EVNWSHWNQN LGIINEDPG KNETYQYYGF SHTVGRLRRD RWSSVVPRVV ELNKNSNPDE VVVPLDSMGN PRCDGHQQGY PRKWRTDDAP LAAALEVLFQ GPSKGEELF TGVVPILVEL DGDVNGHKFS VRGEGEGDAT NGKLTLKFIC TTGKLPVPWP TLVTTLTYGV QCFSRYPDHM K RHDFFKSA MPEGYVQERT ISFKDDGTYK TRAEVKFEGD TLVNRIELKG IDFKEDGNIL GHKLEYNFNS HNVYITADKQ KN GIKANFK IRHNVEDGSV QLADHYQQNT PIGDGPVLLP DNHYLSTQSV LSKDPNEKRD HMVLLEFVTA AGITHGMDEW SHP QFEKGG GSGGGSGGSA WSHPQFEK

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: 4 / 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: [6-[[4-(2,4-dimethyl-1,3-thiazol-5-yl)-1,3-thiazol-2-yl]amino]pyr...

MacromoleculeName: [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
type: ligand / ID: 3 / Number of copies: 4 / Formula: F9M
Molecular weightTheoretical: 572.628 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: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination 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: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.44 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 47803
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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