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- EMDB-36660: Structure of human TRPV4 with antagonist GSK279 -

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Basic information

Entry
Database: EMDB / ID: EMD-36660
TitleStructure of human TRPV4 with antagonist GSK279
Map data
Sample
  • Complex: TRPV4
    • Protein or peptide: Transient receptor potential cation channel subfamily V member 4,3C-GFP
  • Ligand: 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
KeywordsChannel / MEMBRANE PROTEIN
Function / homology
Function and homology information


stretch-activated, monoatomic cation-selective, calcium channel activity / blood vessel endothelial cell delamination / osmosensor activity / vasopressin secretion / positive regulation of striated muscle contraction / positive regulation of macrophage inflammatory protein 1 alpha production / calcium ion import into cytosol / 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 / positive regulation of macrophage inflammatory protein 1 alpha production / calcium ion import into cytosol / negative regulation of brown fat cell differentiation / positive regulation of microtubule depolymerization / hyperosmotic salinity response / 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 / cortical microtubule organization / cellular hypotonic salinity response / osmosensory signaling pathway / multicellular organismal-level water homeostasis / positive regulation of vascular permeability / cellular response to osmotic stress / positive regulation of monocyte chemotactic protein-1 production / cell volume homeostasis / calcium ion import / cell-cell junction assembly / TRP channels / regulation of aerobic respiration / cortical actin cytoskeleton / positive regulation of macrophage chemotaxis / cytoplasmic microtubule / diet induced thermogenesis / beta-tubulin binding / 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 / positive regulation of JNK cascade / calcium ion transmembrane transport / response to insulin / calcium channel activity / cilium / ruffle membrane / positive regulation of inflammatory response / positive regulation of interleukin-6 production / intracellular calcium ion homeostasis / calcium ion transport / actin filament binding / negative regulation of neuron projection development / lamellipodium / glucose homeostasis / actin binding / cellular response to heat / positive regulation of cytosolic calcium ion concentration / growth cone / actin cytoskeleton organization / microtubule binding / positive regulation of ERK1 and ERK2 cascade / calmodulin binding / response to hypoxia / 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
Transient receptor potential cation channel subfamily V member 4 / Transient receptor potential cation channel subfamily V member 1-4 / Transient receptor potential cation channel subfamily V / Ankyrin repeat / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
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: 3.45 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 24, 2023-
Header (metadata) releaseMay 8, 2024-
Map releaseMay 8, 2024-
UpdateJul 24, 2024-
Current statusJul 24, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36660.png

Downloads & links

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Map

FileDownload / File: emd_36660.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
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-1.8987535 - 3.294121
Average (Standard dev.)0.0013209076 (±0.0820909)
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_36660_half_map_1.map
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Half map: #1

Fileemd_36660_half_map_2.map
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Sample components

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Entire : TRPV4

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

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Supramolecule #1: TRPV4

SupramoleculeName: TRPV4 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #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: 1-({(5S,7S)-3-[5-(2-hydroxypropan-2-yl)pyrazin-2-yl]-7-methyl-2-o...

MacromoleculeName: 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
Molecular weightTheoretical: 460.528 Da
Chemical component information

ChemComp-XPW:
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

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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

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.45 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 206979
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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