Tikhonova, I., Zhang, X., Guseinov, A.-A., Jenkins, L. , Li, K., Milligan, G. and Zhang, C. (2024) Structural basis for the ligand recognition and signaling of free fatty acid receptors. Science Advances, 10(2), eadj2384. (doi: 10.1126/sciadv.adj2384) (PMID:38198545)
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Abstract
Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein–coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 are activated by long-chain fatty acids, while FFA2 and FFA3 respond to short-chain fatty acids generated by intestinal microbiota. FFA1, FFA2, and FFA4 are potential drug targets for metabolic and inflammatory conditions. Here, we determined the active structures of FFA1 and FFA4 bound to docosahexaenoic acid, FFA4 bound to the synthetic agonist TUG-891, and butyrate-bound FFA2, each complexed with an engineered heterotrimeric Gq protein (miniGq), by cryo–electron microscopy. Together with computational simulations and mutagenesis studies, we elucidated the similarities and differences in the binding modes of fatty acid ligands to their respective GPCRs. Our findings unveiled distinct mechanisms of receptor activation and G protein coupling. We anticipate that these outcomes will facilitate structure-based drug development and underpin future research on this group of GPCRs.
| Item Type: | Articles |
|---|---|
| Additional Information: | Funding: This work was supported by the NIH grant R35GM128641 to C.Z., the Medical Research Council (UK) grant MR/X010198/1 to G.M., and the Biotechnology and Biological Sciences Research Council (UK) grants BB/R001480/1 and BB/S000453/1 to G.M. and BB/R007101/1 to I.G.T. A.-A.G.’s PhD study is supported by the MSCA COFUND CITI-GENS Programme funded by the E.U. Horizon 2020 research and innovation programme (grant agreement no. 945231). This project made use of computational time on Kelvin-2 supported by Engineering and Physical Sciences Research Council (EPSRC) (grant no. EP/T022175/1 and EP/W03204X/1) and ARCHER2 granted via the U.K. High-End Computing Consortium for Biomolecular Simulation, HECBioSim (www.hecbiosim.ac.uk), supported by EPSRC (grant no. EP/R029407/1 and EP/W03204X/1). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Milligan, Professor Graeme and Jenkins, Mrs Laura |
| Creator Roles: | Jenkins, L.Methodology, Investigation, Visualization Milligan, G.Conceptualization, Methodology, Supervision, Writing – review and editing |
| Authors: | Tikhonova, I., Zhang, X., Guseinov, A.-A., Jenkins, L., Li, K., Milligan, G., and Zhang, C. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
| Journal Name: | Science Advances |
| Publisher: | American Association for the Advancement of Science |
| ISSN: | 2375-2548 |
| ISSN (Online): | 2375-2548 |
| Copyright Holders: | Copyright © 2024 the Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science |
| First Published: | First published in Science Advances 10(2):eadj2384 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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