9DGI
Cannabinoid receptor 1-Gi complex with novel ligand
Summary for 9DGI
| Entry DOI | 10.2210/pdb9dgi/pdb |
| EMDB information | 29898 46828 |
| Descriptor | Cannabinoid receptor 1, methyl (2R)-2-({(1M)-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonyl}amino)-2-(thiophen-2-yl)propanoate (2 entities in total) |
| Functional Keywords | gpcr, g protein, gi, cannabinoid receptor, cb1, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 56115.97 |
| Authors | Tummino, T.A.,Iliopoulos-Tsoutsouvas, C.,Braz, J.M.,O'Brien, E.S.,Krishna Kumar, K.,Makriyannis, M.,Basbaum, A.I.,Shoichet, B.K. (deposition date: 2024-09-02, release date: 2025-04-30, Last modification date: 2025-05-07) |
| Primary citation | Tummino, T.A.,Iliopoulos-Tsoutsouvas, C.,Braz, J.M.,O'Brien, E.S.,Stein, R.M.,Craik, V.,Tran, N.K.,Ganapathy, S.,Liu, F.,Shiimura, Y.,Tong, F.,Ho, T.C.,Radchenko, D.S.,Moroz, Y.S.,Rosado, S.R.,Bhardwaj, K.,Benitez, J.,Liu, Y.,Kandasamy, H.,Normand, C.,Semache, M.,Sabbagh, L.,Glenn, I.,Irwin, J.J.,Kumar, K.K.,Makriyannis, A.,Basbaum, A.I.,Shoichet, B.K. Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects. Nat Commun, 16:2237-2237, 2025 Cited by PubMed 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 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. PubMed: 40044644DOI: 10.1038/s41467-025-57136-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.35 Å) |
Structure validation
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