Molecular insights into GPR55 modulation reveal an atypical activation mechanism and glycosylation-dependent efficacy regulation.

Cryo-EM structures of GPR55 reveal an atypical activation mechanism, and a glycosylation-site mutation converts CID16020046 into a potent agonist enabling active-state co-structure with G13.

• Why it matters: Understanding GPR55 lipid activation is limited by suboptimal chemical probes, and the receptor’s activation mechanism remains unclear.
• What they did: Cryo-EM determined inactive and active states of GPR55, using CID16020046 to design BI-8310; glycosylation-site mutation enabled active, G13-bound co-structure, supported by mutagenesis, N-glycoproteomics, and HDX-MS.
• The result: Comparative analysis of the same ligand across states shows activation diverging from typical helix VI outward movement, establishing a basis for targeted GPR55 modulation in pathophysiological conditions.