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- EMDB-76465: Cryo-EM structure of human cannabinoid receptor 2-Gi complex with... -

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Entry
Database: EMDB / ID: EMD-76465
TitleCryo-EM structure of human cannabinoid receptor 2-Gi complex with agonist '1029
Map data
Sample
  • Complex: Complex of the human cannabinoid receptor 2 with heterotrimeric Gi1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Cannabinoid receptor 2
  • Ligand: methyl N-[4-ethyl-3-(morpholine-4-sulfonyl)benzoyl]-N-hexylglycinate
  • Ligand: water
KeywordsHuman cannabinoid receptor 2 / CNR2 / CB2 receptor / Gi1 / Agonist-bound state / AM12435-bound complex / Active-state GPCR / Class A rhodopsin-like receptor / Cryo-electron microscopy structure / MEMBRANE PROTEIN
Function / homology
Function and homology information


trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of mast cell activation / negative regulation of synaptic transmission, GABAergic / cannabinoid receptor activity / negative regulation of action potential / 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 / adenylate cyclase inhibitor activity ...trans-synaptic signaling by endocannabinoid, modulating synaptic transmission / negative regulation of mast cell activation / negative regulation of synaptic transmission, GABAergic / cannabinoid receptor activity / negative regulation of action potential / 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 / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / 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 / response to amphetamine / cellular response to forskolin / mast cell degranulation / regulation of mitotic spindle organization / chemokine-mediated signaling pathway / Regulation of insulin secretion / neuropeptide signaling pathway / 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-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-inhibiting 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) / G beta:gamma signalling through BTK / photoreceptor disc membrane / GDP binding / 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 / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / cellular response to prostaglandin E stimulus / 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 / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / retina development in camera-type eye / fibroblast proliferation / GTPase binding / G protein activity / midbody / response to lipopolysaccharide / 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 / G alpha (q) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / response to ethanol / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / perikaryon / Ras protein signal transduction / cell population proliferation / postsynaptic membrane / Extra-nuclear estrogen signaling / ciliary basal body / immune response / inflammatory response / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / dendrite
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
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsSacco M / Wu C / Singal B / Skiniotis G
Funding support United States, 1 items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA) United States
CitationJournal: J Med Chem / Year: 2026
Title: Library Docking for Cannabinoid-2 Receptor Ligands.
Authors: Moira M Rachman / Christos Iliopoulos-Tsoutsouvas / Michael D Sacco / Xinyu Xu / Cheng-Guo Wu / Emma Santos / Isabella S Glenn / Lu Paris / Michelle K Cahill / Suthakar Ganapathy / Tia A ...Authors: Moira M Rachman / Christos Iliopoulos-Tsoutsouvas / Michael D Sacco / Xinyu Xu / Cheng-Guo Wu / Emma Santos / Isabella S Glenn / Lu Paris / Michelle K Cahill / Suthakar Ganapathy / Tia A Tummino / Yurii S Moroz / Dmytro S Radchenko / Meri Okorie / Vivianne L Tawfik / John J Irwin / Alexandros Makriyannis / Georgios Skiniotis / Brian K Shoichet /
Abstract: Cannabinoid receptors are both therapeutically attractive and are interesting model systems for structure-based methods. Here we investigated topical questions in library docking using the CB2 ...Cannabinoid receptors are both therapeutically attractive and are interesting model systems for structure-based methods. Here we investigated topical questions in library docking using the CB2 receptor. While a CB1R docking campaign found potent but nonselective ligands, here subtype selective ligands were found by targeting polar residues. Hit rates and hit affinities improved with library size, but docking against active and inactive receptor states did not reliably bias toward agonists or antagonists. Cryo-EM structures of two of the new agonists superposed well on the docking predictions. Structure-based optimization led to 10- to 140-fold improvements within three series, consistent with well-behaved ligands. Hit rates with an explicit 2.6 billion molecule library resembled those of an implied 11 billion molecule library from a building-block method, supporting the latter's ability to explore this space, though higher affinities were discovered from the explicit set. Implications for future studies are considered.
History
DepositionApr 7, 2026-
Header (metadata) releaseJul 15, 2026-
Map releaseJul 15, 2026-
UpdateJul 15, 2026-
Current statusJul 15, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76465.png

Downloads & links

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Map

FileDownload / File: emd_76465.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.96 Å/pix.
x 288 pix.
= 276.48 Å		0.96 Å/pix.
x 288 pix.
= 276.48 Å		0.96 Å/pix.
x 288 pix.
= 276.48 Å

Surface

Projections

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.145
Minimum - Maximum-0.41994852 - 0.7339649
Average (Standard dev.)-0.00036225756 (±0.012899952)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 276.47998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_76465_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_76465_half_map_2.map
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Sample components

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Entire : Complex of the human cannabinoid receptor 2 with heterotrimeric Gi1

EntireName: Complex of the human cannabinoid receptor 2 with heterotrimeric Gi1
Components
  • Complex: Complex of the human cannabinoid receptor 2 with heterotrimeric Gi1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Cannabinoid receptor 2
  • Ligand: methyl N-[4-ethyl-3-(morpholine-4-sulfonyl)benzoyl]-N-hexylglycinate
  • Ligand: water

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Supramolecule #1: Complex of the human cannabinoid receptor 2 with heterotrimeric Gi1

SupramoleculeName: Complex of the human cannabinoid receptor 2 with heterotrimeric Gi1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.414047 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.534062 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV ...String:
MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD IN AICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAG HDNRVS CLGVTDDGMA VATGSWDSFL KIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Cannabinoid receptor 2

MacromoleculeName: Cannabinoid receptor 2 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.442398 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDENL YFQGMEECWV TEIANGSKDG LDSNPMKDYM ILSGPQKTAV AVLCTLLGLL SALENVAVLY LILSSHQLRR KPSYLFIGS LAGADFLASV VFACSFVNFH VFHGVDSKAV FLLKIGSVTM TFTASVGSLL LTAIDRYLCL RYPPSYKALL T RGRALVTL ...String:
DYKDDDDENL YFQGMEECWV TEIANGSKDG LDSNPMKDYM ILSGPQKTAV AVLCTLLGLL SALENVAVLY LILSSHQLRR KPSYLFIGS LAGADFLASV VFACSFVNFH VFHGVDSKAV FLLKIGSVTM TFTASVGSLL LTAIDRYLCL RYPPSYKALL T RGRALVTL GIMWVLSALV SYLPLMGWTC CPRPCSELFP LIPNDYLLSW LLFIAFLFSG IIYTYGHVLW KAHQHVASLS GH QDRQVPG MARMRLDVRL AKTLGLVLAV LLICWFPVLA LMAHSLATTL SDQVKKAFAF CSMLCLINSM VNPVIYALRS GEI RSSAHH CLAHWKKCVR GLGSEAKEEA PRSSVTETEA DGKITPWPDS RDLDLSDC

UniProtKB: Cannabinoid receptor 2

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Macromolecule #5: methyl N-[4-ethyl-3-(morpholine-4-sulfonyl)benzoyl]-N-hexylglycinate

MacromoleculeName: methyl N-[4-ethyl-3-(morpholine-4-sulfonyl)benzoyl]-N-hexylglycinate
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1DB6
Molecular weightTheoretical: 454.58 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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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

Concentration5 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.4 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 9528743
Details: After patch motion correction and patch CTF estimation
CTF correctionSoftware - Name: cryoSPARC
Details: CTF parameters estimated using Patch CTF in cryoSPARC. Phase and amplitude corrections applied during reconstruction and refinement.
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6kpf

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 505644
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
FSC plot (resolution estimation)

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