23IW

Cannabinoid Receptor 1-Gi Complex

This is a non-PDB format compatible entry.

Summary for 23IW

• Entry DOI: 10.2210/pdb23iw/pdb
• EMDB information: 69006
• Descriptor: Cannabinoid receptor 1, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (6 entities in total)
• Functional Keywords: cannabinoid receptor 1, gpcr, membrane protein, active, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 169168.98

Authors

Liao, Y.,Zhang, Y. (deposition date: 2026-02-07, release date: 2026-05-20)

Primary citation

Liao, Y.Y.,Che, J.,Gao, Y.T.,Xue, J.,Li, L.,Wu, L.L.,Hu, J.X.,Hu, M.T.,Xie, L.,Zhang, H.,Shen, D.D.,Dong, Y.,Zang, S.,Zhang, N.,Wang, H.,Zhang, Y.,Dong, X.,Li, X.M.
Rational design of G i -biased CB1 agonist with reduced side effects.
Cell, 2026

PubMed Abstract: The cannabinoid receptor 1 (CB1) has emerged as a promising candidate for next-generation non-opioid therapies. However, the development of therapeutics targeting CB1 has been consistently hindered by significant adverse effects. Here, through structure-activity relationship analyses focused on biased signaling, we rationally design two G-biased CB1 agonists, LZD503 and LZD505. Our design strategy employed structural spatial tuning of the agonist scaffold to disrupt specific molecular interactions and minimize steric conflicts with critical tip residues within the ligand-binding pocket, thereby promoting preferential G-pathway signaling. Cryo-electron microscopy structures of the CB1-G-protein complexes bound to these designed agonists confirmed that their anticipated conformational poses favored G-biased signaling. Both designed compounds demonstrated promising results by alleviating pain and mitigating unwanted responses in mice. The elucidated CB1 complex structures and the resulting insights establish a comprehensive framework for the structure-guided development of innovative CB1-targeted analgesics with reduced adverse effect profiles.

PubMed: 41980782
DOI: 10.1016/j.cell.2026.03.020

Experimental method

ELECTRON MICROSCOPY (2.42 Å)