12IZ

Cryo-EM structure of human cannabinoid receptor 2-Gi complex with agonist '5249

This is a non-PDB format compatible entry.

Summary for 12IZ

• Entry DOI: 10.2210/pdb12iz/pdb
• EMDB information: 76464
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: human 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
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 158580.33

Authors

Sacco, M.,Wu, C.,Singal, B.,Skiniotis, G. (deposition date: 2026-04-07, release date: 2026-07-15)

Primary citation

Rachman, M.M.,Iliopoulos-Tsoutsouvas, C.,Sacco, M.D.,Xu, X.,Wu, C.G.,Santos, E.,Glenn, I.S.,Paris, L.,Cahill, M.K.,Ganapathy, S.,Tummino, T.A.,Moroz, Y.S.,Radchenko, D.S.,Okorie, M.,Tawfik, V.L.,Irwin, J.J.,Makriyannis, A.,Skiniotis, G.,Shoichet, B.K.
Library Docking for Cannabinoid-2 Receptor Ligands.
J.Med.Chem., 2026

PubMed 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 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.

PubMed: 42397716
DOI: 10.1021/acs.jmedchem.6c00835

Experimental method

ELECTRON MICROSCOPY (2.72 Å)