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Open data
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Basic information
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Title | Structure of human TRPV4 with antagonist GSK279 | |||||||||
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![]() | Channel / MEMBRANE PROTEIN | |||||||||
Function / homology | ![]() 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 / 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 / cellular hypotonic response / cellular hypotonic salinity response / multicellular organismal-level water homeostasis / osmosensory signaling pathway / positive regulation of vascular permeability / cellular response to osmotic stress / cell volume homeostasis / positive regulation of monocyte chemotactic protein-1 production / calcium ion import / cell-cell junction assembly / TRP channels / regulation of aerobic respiration / cortical actin cytoskeleton / positive regulation of macrophage chemotaxis / beta-tubulin binding / cytoplasmic microtubule / diet induced thermogenesis / microtubule polymerization / alpha-tubulin binding / monoatomic cation channel activity / response to mechanical stimulus / SH2 domain binding / filopodium / actin filament organization / adherens junction / protein kinase C binding / calcium ion transmembrane transport / positive regulation of JNK cascade / response to insulin / calcium channel activity / cilium / ruffle membrane / intracellular calcium ion homeostasis / positive regulation of inflammatory response / positive regulation of interleukin-6 production / calcium ion transport / actin filament binding / negative regulation of neuron projection development / lamellipodium / glucose homeostasis / actin binding / positive regulation of cytosolic calcium ion concentration / cellular response to heat / growth cone / actin cytoskeleton organization / microtubule binding / positive regulation of ERK1 and ERK2 cascade / response to hypoxia / calmodulin binding / apical plasma membrane / focal adhesion / lipid binding / protein kinase binding / negative regulation of transcription by RNA polymerase II / cell surface / endoplasmic reticulum / ATP binding / identical protein binding / membrane / metal ion binding / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.45 Å | |||||||||
![]() | Fan J / Lei X | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 59.6 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.9 KB 14.9 KB | Display Display | ![]() |
Images | ![]() | 119 KB | ||
Filedesc metadata | ![]() | 6.3 KB | ||
Others | ![]() ![]() | 59.2 MB 59.2 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8ju6MC ![]() 8ju5C ![]() 8jviC ![]() 8jvjC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.04 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #2
File | emd_36660_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_36660_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : TRPV4
Entire | Name: TRPV4 |
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Components |
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-Supramolecule #1: TRPV4
Supramolecule | Name: TRPV4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 400 KDa |
-Macromolecule #1: Transient receptor potential cation channel subfamily V member 4,...
Macromolecule | Name: 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 |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 128.628547 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #2: 1-({(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-o...
Macromolecule | Name: 1-({(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl}methyl)-1H-benzimidazole-6-carbonitrile type: ligand / ID: 2 / Number of copies: 4 / Formula: XPW |
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Molecular weight | Theoretical: 460.528 Da |
Chemical component information | ![]() ChemComp-XPW: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 60.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | 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
Startup model | Type of model: OTHER |
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Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 206979 |
Initial angle assignment | Type: RANDOM ASSIGNMENT |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |