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- EMDB-28976: Cryo-EM structure of the human TRPV4 in complex with GSK1016790A -

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Basic information

Entry
Database: EMDB / ID: EMD-28976
TitleCryo-EM structure of the human TRPV4 in complex with GSK1016790A
Map datamain_map
Sample
  • Complex: The complex of human TRPV4 with RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4
  • Ligand: N-[(2S)-1-{4-[N-(2,4-dichlorobenzene-1-sulfonyl)-L-seryl]piperazin-1-yl}-4-methyl-1-oxopentan-2-yl]-1-benzothiophene-2-carboxamide
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsTRPV4 / RhoA / GSK1016790A / MEMBRANE PROTEIN
Function / homology
Function and homology information


blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / 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 ...blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / stretch-activated, monoatomic cation-selective, calcium channel activity / 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 / 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 / cellular hypotonic response / Roundabout signaling pathway / negative regulation of intracellular steroid hormone receptor signaling pathway / Axonal growth inhibition (RHOA activation) / Axonal growth stimulation / cellular hypotonic salinity response / regulation of neural precursor cell proliferation / cleavage furrow formation / 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 / negative regulation of cell size / positive regulation of vascular permeability / beta selection / establishment of epithelial cell apical/basal polarity / regulation of modification of postsynaptic structure / RHO GTPases Activate ROCKs / negative regulation of oxidative phosphorylation / negative regulation of motor neuron apoptotic process / cellular response to osmotic stress / calcium ion import / osmosensory signaling pathway / RHO GTPases activate CIT / cell volume homeostasis / PCP/CE pathway / Sema4D induced cell migration and growth-cone collapse / RHO GTPases activate KTN1 / 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 / positive regulation of alpha-beta T cell differentiation / ossification involved in bone maturation / odontogenesis / motor neuron apoptotic process / positive regulation of leukocyte adhesion to vascular endothelial cell / PI3K/AKT activation / wound healing, spreading of cells / apical junction complex / regulation of neuron projection development / 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 / beta-tubulin binding / stress fiber assembly / RHOC GTPase cycle / diet induced thermogenesis / positive regulation of cytokinesis / microtubule polymerization / androgen receptor signaling pathway / cerebral cortex cell migration / cellular response to cytokine stimulus / cytoplasmic microtubule / ERBB2 Regulates Cell Motility / cleavage furrow / semaphorin-plexin signaling pathway / Rho protein signal transduction / ficolin-1-rich granule membrane / alpha-tubulin binding / mitotic spindle assembly
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.47 Å
AuthorsKwon DH / Lee S-Y / Zhang F
Funding support1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)
CitationJournal: Nat Commun / Year: 2023
Title: TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.
Authors: Do Hoon Kwon / Feng Zhang / Brett A McCray / Shasha Feng / Meha Kumar / Jeremy M Sullivan / Wonpil Im / Charlotte J Sumner / Seok-Yong Lee /
Abstract: Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, ...Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures of human TRPV4 in complex with RhoA in the ligand-free, antagonist-bound closed, and agonist-bound open states. These structures reveal the mechanism of ligand-dependent TRPV4 gating. Channel activation is associated with rigid-body rotation of the intracellular ankyrin repeat domain, but state-dependent interaction with membrane-anchored RhoA constrains this movement. Notably, many residues at the TRPV4-RhoA interface are mutated in disease and perturbing this interface by introducing mutations into either TRPV4 or RhoA increases TRPV4 channel activity. Together, these results suggest that RhoA serves as an auxiliary subunit for TRPV4, regulating TRPV4-mediated calcium homeostasis and disruption of TRPV4-RhoA interactions can lead to TRPV4-related neuromuscular disease. These insights will help facilitate TRPV4 therapeutics development.
History
DepositionDec 1, 2022-
Header (metadata) releaseJul 12, 2023-
Map releaseJul 12, 2023-
UpdateJun 19, 2024-
Current statusJun 19, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28976.png

Downloads & links

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Map

FileDownload / File: emd_28976.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationmain_map
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.313
Minimum - Maximum-2.3622894 - 4.176428
Average (Standard dev.)0.0099778995 (±0.09055017)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 276.48 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half A

Fileemd_28976_half_map_1.map
AnnotationHalf_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half B

Fileemd_28976_half_map_2.map
AnnotationHalf_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : The complex of human TRPV4 with RhoA

EntireName: The complex of human TRPV4 with RhoA
Components
  • Complex: The complex of human TRPV4 with RhoA
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4
  • Ligand: N-[(2S)-1-{4-[N-(2,4-dichlorobenzene-1-sulfonyl)-L-seryl]piperazin-1-yl}-4-methyl-1-oxopentan-2-yl]-1-benzothiophene-2-carboxamide
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: The complex of human TRPV4 with RhoA

SupramoleculeName: The complex of human TRPV4 with RhoA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 450 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
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 102.057797 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 LENSLEVLFQ GPDYKDDDD KAHHHHHHHH HH

UniProtKB: Transient receptor potential cation channel subfamily V member 4

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Macromolecule #2: N-[(2S)-1-{4-[N-(2,4-dichlorobenzene-1-sulfonyl)-L-seryl]piperazi...

MacromoleculeName: N-[(2S)-1-{4-[N-(2,4-dichlorobenzene-1-sulfonyl)-L-seryl]piperazin-1-yl}-4-methyl-1-oxopentan-2-yl]-1-benzothiophene-2-carboxamide
type: ligand / ID: 2 / Number of copies: 4 / Formula: XQ3
Molecular weightTheoretical: 655.613 Da
Chemical component information

ChemComp-XQ3:
N-[(2S)-1-{4-[N-(2,4-dichlorobenzene-1-sulfonyl)-L-seryl]piperazin-1-yl}-4-methyl-1-oxopentan-2-yl]-1-benzothiophene-2-carboxamide

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Macromolecule #3: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 3 / Number of copies: 4 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 281.15 K / Instrument: LEICA EM GP

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Electron microscopy

MicroscopeFEI TITAN
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 81000
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7lp9

Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.47 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 207645

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