Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Thursday Speaker Abstracts

STRUCTURE, FUNCTION AND DRUG INTERACTIONS OF ORPHAN GPCRS Herbert Nar ; Antonio Manuel Liaci; Tobias Claff; Dietmar Weichert ; Rebecca Ebenhoch; Boehringer Ingelheim GmbH & Co. KG, Medicinal Chemistry, Biberach, Germany Structural and functional studies involving the orphan GPCRs GPR55 and GPR75 will be presented. For GPR55, a lipid-activated G protein-coupled receptor (GPCR) implicated in metabolism, inflammation, and neurodegeneration, we determined 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 unprecedented insights into an atypical activation mechanism that diverges from the typical helix VI outward movement observed in other GPCRs. These results establish a basis for targeted modulation of GPR55 in pathophysiological conditions. GPR75 is one of the most promising emerging targets for the treatment of obesity and related co-morbidities, as its loss of function directly correlates with a decreased body mass index (BMI) in humans. To date, little is known about the structure and underlying biology of GPR75, which has low homology to other GPCRs. We describe the cryoEM structure of ICL3-BRIL-fused, unliganded human GPR75, together with functional data on G-protein coupling and effects of its putative ligands. GPR75 is present in an active-like state probably induced by the structure of its extracellular loop 2 (ECL2) which folds back deeply into the orthosteric pocket. This feature is important for both receptor integrity and signaling, as shown by mutagenesis studies. This structural finding is consistent with moderate constitutive activity for G α i1. Furthermore, functional data indicate that the putative ligands 20-HETE and CCL5 have no measurable effect on GPR75.

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