9CM3
Cryo-EM structure of Gq-coupled FFA2 in complex with TUG-1375 and compound 187
This is a non-PDB format compatible entry.
Summary for 9CM3
| Entry DOI | 10.2210/pdb9cm3/pdb |
| EMDB information | 45738 |
| Descriptor | Guanine nucleotide-binding protein G(q) subunit alpha, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, scFv16, ... (9 entities in total) |
| Functional Keywords | gpcr, agonist, membrane protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 167954.80 |
| Authors | Zhang, X.,Tikhonova, I.,Milligan, G.,Zhang, C. (deposition date: 2024-07-12, release date: 2025-06-25, Last modification date: 2025-08-13) |
| Primary citation | Zhang, X.,Guseinov, A.A.,Jenkins, L.,Valentini, A.,Marsango, S.,Schultz-Knudsen, K.,Ulven, T.,Rexen Ulven, E.,Tikhonova, I.G.,Milligan, G.,Zhang, C. Allosteric modulation and biased signalling at free fatty acid receptor 2. Nature, 643:1428-1438, 2025 Cited by PubMed Abstract: Free fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that is a primary sensor for short-chain fatty acids produced by gut microbiota. Consequently, FFA2 is a promising drug target for immunometabolic disorders. Here we report cryogenic electronic microscopy structures of FFA2 in complex with two G proteins and three distinct classes of positive allosteric modulators (PAMs), and describe noncanonical activation mechanisms that involve conserved structural features of class A GPCRs. Two PAMs disrupt the E/DRY activation microswitch and stabilize the conformation of intracellular loop 2 by binding to lipid-facing pockets near the cytoplasmic side of the receptor. By contrast, the third PAM promotes the separation of transmembrane helices 6 and 7 by interacting with transmembrane helix 6 at the receptor-lipid interface. Molecular dynamic simulations and mutagenesis experiments confirm these noncanonical activation mechanisms. Furthermore, we demonstrate the molecular basis for the G versus G bias, which is due to distinct conformations of intracellular loop 2 stabilized by different PAMs. These findings provide a framework for the design of tailored GPCR modulators, with implications that extend beyond FFA2 to the broader field of GPCR drug discovery. PubMed: 40533560DOI: 10.1038/s41586-025-09186-6 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.06 Å) |
Structure validation
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