9TC9
Active-state structure of the GPR55-N171Q mutant in complex with G13 and BI-6229
This is a non-PDB format compatible entry.
Summary for 9TC9
| Entry DOI | 10.2210/pdb9tc9/pdb |
| EMDB information | 55778 |
| Descriptor | Guanine nucleotide-binding protein G(i) subunit alpha-2,Guanine nucleotide-binding protein subunit alpha-13, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ScFv16, ... (6 entities in total) |
| Functional Keywords | gpcr, g protein-coupled receptor, gpr55, g13, efficacy-switch, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 180690.05 |
| Authors | Claff, T.,Ebenhoch, R.,Kley, J.T.,Weichert, D. (deposition date: 2025-11-20, release date: 2026-11-04) |
| Primary citation | Claff, T.,Demalgiriya-Gamage, C.,Mahardhika, A.B.,Stamos, N.A.,Bangnowski, F.,Sun, X.,Durr, K.L.,Robinson, C.V.,Haney, R.,Frego, L.,Nar, H.,Muller, C.E.,Ebenhoch, R.,Kley, J.T.,Weichert, D. Molecular insights into GPR55 modulation reveal an atypical activation mechanism and glycosylation-dependent efficacy regulation. Nat Commun, 17:-, 2026 Cited by PubMed 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, G-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. PubMed: 42926240DOI: 10.1038/s41467-026-78538-1 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.88 Å) |
Structure validation
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