Molecular insights into GPR55 modulation reveal an atypical activation mechanism and glycosylation-dependent efficacy regulation
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
- Molecular mechanism of dynamic regulation of the proNGF/NGF ratio in controlling hair follicle cycle transition in liaoning cashmere goats
- Molecular mechanism of KRAS binding to BRAF and its regulation by the BRAF-specific region
- Multi-omics reveals divergent regulation of anthocyanin glycosylation and gibberellin biosynthesis underlying leaf variegation in Saxifraga stolonifera
- Molecular Determinants of Sequence-Dependent N-glycosylation by the Human Oligosaccharyltransferase
- Catalytic mechanism and allosteric regulation of an oligomeric (p)ppGpp synthetase by an alarmone.
BibTeX
@article{claff2026molecular,
title = {{Molecular insights into GPR55 modulation reveal an atypical activation mechanism and glycosylation-dependent efficacy regulation}},
author = {Tobias Claff and Chamalee Demalgiriya-Gamage and Andhika B. Mahardhika and Nikolaos Angelos Stamos and Frederik Bangnowski and Xue Sun and Katharina L. Dürr and Carol V. Robinson and Rainer Haney and Lee Frego and Herbert Nar and Christa E. Müller and Rebecca Ebenhoch and Jörg T. Kley and Dietmar Weichert},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78538-1},
url = {https://www.nature.com/articles/s41467-026-78538-1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Molecular insights into GPR55 modulation reveal an atypical activation mechanism and glycosylation-dependent efficacy regulation
AU - Tobias Claff
AU - Chamalee Demalgiriya-Gamage
AU - Andhika B. Mahardhika
AU - Nikolaos Angelos Stamos
AU - Frederik Bangnowski
AU - Xue Sun
AU - Katharina L. Dürr
AU - Carol V. Robinson
AU - Rainer Haney
AU - Lee Frego
AU - Herbert Nar
AU - Christa E. Müller
AU - Rebecca Ebenhoch
AU - Jörg T. Kley
AU - Dietmar Weichert
PY - 2026
DA - 2026/10/24
JO - Nature Communications
DO - 10.1038/s41467-026-78538-1
UR - https://www.nature.com/articles/s41467-026-78538-1
AB - 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.
SN - 2041-1723
ER -