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- PDB-9dgi: Cannabinoid receptor 1-Gi complex with novel ligand -

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Basic information

Entry
Database: PDB / ID: 9dgi
TitleCannabinoid receptor 1-Gi complex with novel ligand
ComponentsCannabinoid receptor 1
KeywordsSIGNALING PROTEIN / GPCR / G protein / Gi / cannabinoid receptor / CB1
Function / homology
Function and homology information


cannabinoid signaling pathway / regulation of penile erection / negative regulation of dopamine secretion / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / negative regulation of fatty acid beta-oxidation / negative regulation of serotonin secretion / positive regulation of acute inflammatory response to antigenic stimulus / regulation of feeding behavior ...cannabinoid signaling pathway / regulation of penile erection / negative regulation of dopamine secretion / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / negative regulation of fatty acid beta-oxidation / negative regulation of serotonin secretion / positive regulation of acute inflammatory response to antigenic stimulus / regulation of feeding behavior / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of action potential / positive regulation of blood pressure / positive regulation of fever generation / Class A/1 (Rhodopsin-like receptors) / axonal fasciculation / regulation of metabolic process / regulation of synaptic transmission, GABAergic / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / maternal process involved in female pregnancy / regulation of synaptic transmission, glutamatergic / negative regulation of blood pressure / response to nutrient / regulation of insulin secretion / GABA-ergic synapse / response to nicotine / response to cocaine / G protein-coupled receptor activity / positive regulation of neuron projection development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / memory / adenylate cyclase-activating G protein-coupled receptor signaling pathway / glucose homeostasis / actin cytoskeleton / presynaptic membrane / growth cone / G alpha (i) signalling events / spermatogenesis / response to lipopolysaccharide / response to ethanol / mitochondrial outer membrane / positive regulation of apoptotic process / membrane raft / glutamatergic synapse / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
Cannabinoid receptor type 1 / Cannabinoid receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / 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)
Similarity search - Domain/homology
: / Cannabinoid receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.35 Å
AuthorsTummino, T.A. / Iliopoulos-Tsoutsouvas, C. / Braz, J.M. / O'Brien, E.S. / Krishna Kumar, K. / Makriyannis, M. / Basbaum, A.I. / Shoichet, B.K.
Funding support United States, 1items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA)HR0011-19-2-0020 United States
CitationJournal: Nat Commun / Year: 2025
Title: Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects.
Authors: Tia A Tummino / Christos Iliopoulos-Tsoutsouvas / Joao M Braz / Evan S O'Brien / Reed M Stein / Veronica Craik / Ngan K Tran / Suthakar Ganapathy / Fangyu Liu / Yuki Shiimura / Fei Tong / ...Authors: Tia A Tummino / Christos Iliopoulos-Tsoutsouvas / Joao M Braz / Evan S O'Brien / Reed M Stein / Veronica Craik / Ngan K Tran / Suthakar Ganapathy / Fangyu Liu / Yuki Shiimura / Fei Tong / Thanh C Ho / Dmytro S Radchenko / Yurii S Moroz / Sian Rodriguez Rosado / Karnika Bhardwaj / Jorge Benitez / Yongfeng Liu / Herthana Kandasamy / Claire Normand / Meriem Semache / Laurent Sabbagh / Isabella Glenn / John J Irwin / Kaavya Krishna Kumar / Alexandros Makriyannis / Allan I Basbaum / Brian K Shoichet /
Abstract: Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for the cannabinoid-1 receptor (CB1R), we dock 74 million tangible ...Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for the cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones for de novo synthesis and testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (K = 0.7 µM) leads to '1350, a 0.95 nM ligand and a full CB1R agonist of G signaling. A cryo-EM structure of '1350 in complex with CB1R-G confirms its predicted docked pose. The lead agonist is strongly analgesic in male mice, with a 2-20-fold therapeutic window over hypolocomotion, sedation, and catalepsy and no observable conditioned place preference. These findings suggest that unique cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from analgesia, supporting the further development of cannabinoids as pain therapeutics.
History
DepositionSep 2, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 30, 2025Provider: repository / Type: Initial release
Revision 1.1May 7, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Cannabinoid receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,1162
Polymers55,6791
Non-polymers4371
Water00
1


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

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Components

#1: Protein Cannabinoid receptor 1 / CB1 / CANN6


Mass: 55678.535 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CNR1, CNR
Production host: Spodoptera aff. frugiperda 1 BOLD-2017 (butterflies/moths)
References: UniProt: P21554
#2: Chemical ChemComp-YVF / methyl (2R)-2-({(1M)-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonyl}amino)-2-(thiophen-2-yl)propanoate


Mass: 437.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H18F3N3O3S / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: Signaling complex of the cannabinoid receptor 1 bound to Gi
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 56.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 465411 / Symmetry type: POINT

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