Related Experiment Video
Updated: Oct 26, 2026

BRET-based G Protein Biosensors for Measuring G Protein-Coupled Receptor Activity in Live Cells
Published on: November 7, 2025
Molecular insights into GPR55 modulation reveal an atypical activation mechanism and glycosylation-dependent efficacy
Tobias Claff1,2, Chamalee Demalgiriya-Gamage3, Andhika B Mahardhika4
1Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Birkendorfer Str. 65, Biberach an der Riß, Germany. tclaff@uni-bonn.de.
Abstract:
GPR55 is a lipid-activated G protein-coupled receptor (GPCR) implicated in metabolism, inflammation, and neurodegeneration. Lysophosphatidylinositol (LPI) species are proposed as endogenous agonists, but progress in understanding GPR55 function has still been limited by suboptimal chemical probes. Here, we present cryo-electron microscopy (cryo-EM) structures of GPR55 in both inactive and active states. The inactive-state structure bound to the inverse agonist CID16020046 facilitated the rational design of an improved in vitro tool compound, BI-8310. Surprisingly, mutation of a glycosylation site in extracellular loop 2 converted CID16020046 into a potent agonist, enabling co-structure determination of the active, G13-bound receptor. Comparative analysis of both states bound to the same ligand provides insights into an atypical activation mechanism that diverges from the typical helix VI outward movement observed in other GPCRs. Functional mutagenesis, N-glycoproteomics, and hydrogen-deuterium exchange mass spectrometry (HDX-MS) substantiate the findings. These results establish a basis for targeted modulation of GPR55 in pathophysiological conditions.
Related Concept Videos
G Protein-coupled Receptors
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
G Protein-coupled Receptors
GPCRs Regulate Adenylyl Cylase Activity
Two...
GPCR Desensitization
Transducer Mechanism: G Protein–Coupled Receptors
GPCRs are also called heptahelical, 7TM, or...
Activation and Inactivation of G Proteins

