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- PDB-9u7l: G protein-coupled receptor complex -

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Basic information

Entry
Database: PDB / ID: 9u7l
TitleG protein-coupled receptor complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Cannabinoid receptor 2
KeywordsMEMBRANE PROTEIN / G protein-coupled receptor complex
Function / homology
Function and homology information


negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / cannabinoid receptor activity / negative regulation of action potential / negative regulation of synaptic transmission, GABAergic / Class A/1 (Rhodopsin-like receptors) / extrinsic component of cytoplasmic side of plasma membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of eating behavior / response to amphetamine ...negative regulation of mast cell activation / trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / cannabinoid receptor activity / negative regulation of action potential / negative regulation of synaptic transmission, GABAergic / Class A/1 (Rhodopsin-like receptors) / extrinsic component of cytoplasmic side of plasma membrane / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of eating behavior / response to amphetamine / adenylate cyclase inhibitor activity / T cell migration / positive regulation of protein localization to cell cortex / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / mast cell degranulation / chemokine-mediated signaling pathway / neuropeptide signaling pathway / Regulation of insulin secretion / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / response to peptide hormone / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / GDP binding / G beta:gamma signalling through BTK / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / heterotrimeric G-protein complex / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / G-protein beta-subunit binding / extracellular vesicle / response to lipopolysaccharide / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / ciliary basal body / GTPase binding / G protein activity / midbody / Ca2+ pathway / cell cortex / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / response to ethanol / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / perikaryon / Ras protein signal transduction / postsynaptic membrane / Extra-nuclear estrogen signaling / immune response / inflammatory response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / centrosome / GTPase activity / dendrite / synapse / GTP binding / protein-containing complex binding / magnesium ion binding / signal transduction
Similarity search - Function
Cannabinoid receptor type 2 / Cannabinoid receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit ...Cannabinoid receptor type 2 / Cannabinoid receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / 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
Chem-9GF / : / Cannabinoid receptor 2 / 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 G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWang, X.H. / Li, W.M.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis for positive allosteric regulation of CB2 receptor.
Authors: Xuehui Wang / Ye Cai / Xin Yang / Shanquan Wu / Jinghong Xian / Jing Wang / Dongsheng Lei / Weimin Li /
Abstract: The synthetic positive allosteric modulator (PAM) of cannabinoid receptor CB2, Ec21a, exhibits better subtype selectivity and receptor specificity over orthosteric ligands, which holds promise for ...The synthetic positive allosteric modulator (PAM) of cannabinoid receptor CB2, Ec21a, exhibits better subtype selectivity and receptor specificity over orthosteric ligands, which holds promise for treating neuropathic pain and seizure without causing psychotropic side effects mediated by CB1. The poor understanding of allosteric binding site and regulatory mechanism of Ec21a hinders further development of CB2 allosteric modulators. Here, we resolve the cryo-EM structure of CB2 in complex with PAM Ec21a and agonist CP55940, revealing a sandwich-like pattern of ECL2-Ec21a-CP55940, in which Ec21a binds above CP55940 acting as a "plug" and sterically hinders the dissociation of the CP55940. Through structural analysis and cell functional experiments, we find that Ec21a significantly enhances the activation efficiency of CP55940 via increasing and prolonging the interaction between CP55940 and CB2. Furthermore, by assessing the allosteric effects of Ec21a in combination with various agonists, we expand the potential range of ligand pairings and provide a structural framework for the design of bitopic ligands. Our findings address a gap in the understanding of the CB2 allosteric site and offer valuable guidance for the rational design of CB2 allosteric and bitopic ligands.
History
DepositionMar 24, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 12, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
C: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Cannabinoid receptor 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)126,0096
Polymers125,1984
Non-polymers8122
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63096, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37198.656 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein , 1 types, 1 molecules R

#4: Protein Cannabinoid receptor 2 / CB-2 / CB2 / hCB2 / CX5


Mass: 39722.715 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CNR2, CB2A, CB2B / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P34972

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-9GF / 2-[(1R,2R,5R)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol


Mass: 376.573 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H40O3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-A1EOL / ~{N}-[5-bromanyl-1-[(4-fluorophenyl)methyl]-4-methyl-2-oxidanylidene-pyridin-3-yl]cycloheptanecarboxamide


Mass: 435.330 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24BrFN2O2 / Feature type: SUBJECT OF INVESTIGATION

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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

ComponentName: protein A / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 9.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2645 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 64.84 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)
Image scansMovie frames/image: 5

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.6particle selection
2PHENIX1.19.2_4158model refinement
13cryoSPARC4.63D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 108775 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037105
ELECTRON MICROSCOPYf_angle_d0.4719640
ELECTRON MICROSCOPYf_dihedral_angle_d7.012986
ELECTRON MICROSCOPYf_chiral_restr0.041117
ELECTRON MICROSCOPYf_plane_restr0.0051205

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