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- PDB-9ge3: Structure of GPR55 in complex with G13 and endogenous lipid agoni... -

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Basic information

Entry
Database: PDB / ID: 9ge3
TitleStructure of GPR55 in complex with G13 and endogenous lipid agonist lysophosphatidylinositol
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Green fluorescent protein,G-protein coupled receptor 55
  • Single-chain variable fragment ScFv16
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor / GPCR / lipid agonist / cholesterol
Function / homology
Function and homology information


D5 dopamine receptor binding / Rho-activating G protein-coupled receptor signaling pathway / regulation of fibroblast migration / cannabinoid receptor activity / Class A/1 (Rhodopsin-like receptors) / regulation of small GTPase mediated signal transduction / NRAGE signals death through JNK / branching involved in blood vessel morphogenesis / positive regulation of Rho protein signal transduction / negative regulation of vascular associated smooth muscle cell migration ...D5 dopamine receptor binding / Rho-activating G protein-coupled receptor signaling pathway / regulation of fibroblast migration / cannabinoid receptor activity / Class A/1 (Rhodopsin-like receptors) / regulation of small GTPase mediated signal transduction / NRAGE signals death through JNK / branching involved in blood vessel morphogenesis / positive regulation of Rho protein signal transduction / negative regulation of vascular associated smooth muscle cell migration / negative regulation of osteoclast differentiation / negative regulation of vascular associated smooth muscle cell proliferation / CDC42 GTPase cycle / regulation of postsynapse assembly / Rho protein signal transduction / bone resorption / RAC1 GTPase cycle / bioluminescence / guanyl-nucleotide exchange factor activity / generation of precursor metabolites and energy / brush border membrane / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / platelet activation / regulation of blood pressure / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / melanosome / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / regulation of cell shape / Thrombin signalling through proteinase activated receptors (PARs) / G protein activity / GTPase binding / positive regulation of cytosolic calcium ion concentration / Ca2+ pathway / retina development in camera-type eye / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / in utero embryonic development / Ras protein signal transduction / cell differentiation / Extra-nuclear estrogen signaling / cell population proliferation / positive regulation of ERK1 and ERK2 cascade / postsynapse / G protein-coupled receptor signaling pathway / lysosomal membrane / focal adhesion / GTPase activity / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / metal ion binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
G-protein alpha subunit, group 12/13 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit ...G-protein alpha subunit, group 12/13 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / Green fluorescent protein / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein subunit alpha-13 / G-protein coupled receptor 55
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Aequorea victoria (jellyfish)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.87 Å
AuthorsClaff, T. / Ebenhoch, R. / Weichert, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for lipid-mediated activation of G protein-coupled receptor GPR55.
Authors: Tobias Claff / Rebecca Ebenhoch / Jörg T Kley / Aniket Magarkar / Herbert Nar / Dietmar Weichert /
Abstract: GPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, and metabolic diseases. The endogenous activation of lipid GPCRs can be solely ...GPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, and metabolic diseases. The endogenous activation of lipid GPCRs can be solely mediated by membrane components and different lipids have been proposed as endogenous activators of GPR55, such as cannabinoids and lysophosphatidylinositols. Here, we determine high-resolution cryo-electron microscopy structures of the activated GPR55 in complex with heterotrimeric G and two structurally diverse ligands: the putative endogenous agonist 1-palmitoyl-2-lysophosphatidylinositol (LPI) and the synthetic agonist ML184. These results reveal insights into ligand recognition at GPR55, G protein coupling and receptor activation. Notably, an orthosteric binding site opening towards the membrane is observed in both structures, enabling direct interaction of the agonists with membrane lipids. The structural observations are supported by mutagenesis and functional experiments employing G protein dissociation assays. These findings will be of importance for the structure-based development of drugs targeting GPR55.
History
DepositionAug 6, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 5, 2025Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 5, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Mar 19, 2025Group: Data collection / Structure summary / Category: chem_comp / em_admin / Item: _chem_comp.pdbx_synonyms / _em_admin.last_update
Revision 1.1Mar 19, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Experimental summary / Structure summary / Data content type: EM metadata / Category: em_admin / Data content type: EM metadata / EM metadata / Item: _chem_comp.pdbx_synonyms / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein subunit alpha-13
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
F: Single-chain variable fragment ScFv16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Green fluorescent protein,G-protein coupled receptor 55
hetero molecules


Theoretical massNumber of molelcules
Total (without water)175,4867
Polymers174,6925
Non-polymers7942
Water1086
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein subunit alpha-13 / G alpha-13 / G-protein subunit alpha-13


Mass: 26574.400 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNA13 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q14344
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 39418.086 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 8506.765 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Antibody / Protein / Sugars , 3 types, 3 molecules FR

#3: Antibody Single-chain variable fragment ScFv16


Mass: 27068.225 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper)
#5: Protein Green fluorescent protein,G-protein coupled receptor 55


Mass: 73124.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Aequorea victoria (jellyfish), (gene. exp.) Homo sapiens (human)
Gene: GFP, GPR55 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P42212, UniProt: Q9Y2T6
#7: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 7 molecules

#6: Chemical ChemComp-A1IKT / [(2R)-2-oxidanyl-3-[oxidanyl-[(2R,3S,5R,6R)-2,3,4,5,6-pentakis(oxidanyl)cyclohexyl]oxy-phosphoryl]oxy-propyl] hexadecanoate / [(2R)-2-hydroxy-3-[hydroxy-[(2R,3R,5S,6R)-2,3,4,5,6-pentahydroxycyclohexyl]-oxyphosphoryl]oxypropyl] hexadecanoate / 1-hexadecanoyl-sn-glycero-3-phospho-(1'-myo-inositol)


Mass: 572.623 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H49O12P / Feature type: SUBJECT OF INVESTIGATION
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1GPR55 in complex with heterotrimeric G13 protein and endogenous lipid agonist lysophosphatidylinositolCOMPLEX#1-#50MULTIPLE SOURCES
2Guanine nucleotide-binding proteinsCOMPLEX#1-#2, #41RECOMBINANT
3Single-chain variable fragment ScFv16COMPLEX#31RECOMBINANT
4G-protein coupled receptor 55 with a GFP tagCOMPLEX#51RECOMBINANT
Molecular weightValue: 0.18 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Mus musculus (house mouse)10090
44Aequorea victoria (jellyfish)6100
54Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Trichoplusia ni (cabbage looper)7111
33Trichoplusia ni (cabbage looper)7111
44Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal magnification: 130000 X / Nominal defocus max: 3000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 40 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
4cryoSPARCCTF correction
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 15173387
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.87 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 397853 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028750
ELECTRON MICROSCOPYf_angle_d0.45711846
ELECTRON MICROSCOPYf_dihedral_angle_d4.6911222
ELECTRON MICROSCOPYf_chiral_restr0.041334
ELECTRON MICROSCOPYf_plane_restr0.0031495

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