Structural insights into lipid chain-length selectivity and allosteric regulation of FFA2
The free fatty acid receptor 2 (FFA2) is a G protein-coupled receptor (GPCR) that selectively recognizes short-chain fatty acids to regulate metabolic and immune functions. As a promising therapeutic target, FFA2 has been the focus of intensive development of synthetic ligands. However, the mechanisms by which endogenous and synthetic ligands modulate FFA2 activity remain unclear. Here, we present the structures of the human FFA2-Gi complex activated by the synthetic orthosteric agonist TUG-1375 and the positive allosteric modulator/allosteric agonist 4-CMTB, along with the structure of the inactive FFA2 bound to the antagonist GLPG0974. Structural comparisons with FFA1 and mutational studies reveal how FFA2 selects specific fatty acid chain lengths. Moreover, our structures reveal that GLPG0974 functions as an allosteric antagonist by binding adjacent to the orthosteric pocket to block agonist binding, whereas 4-CMTB binds the outer surface of transmembrane helices 6 and 7 to directly activate the receptor. Supported by computational and functional studies, these insights illuminate diverse mechanisms of ligand action, paving the way for precise GPCR-targeted drug design.
Authors
- Asato Kojima
- Toshiki E. Matsui (ORCID: https://orcid.org/0000-0002-2900-5206)
- Masahiro Fukuda (ORCID: https://orcid.org/0000-0002-8824-846X)
- Keisuke Saito (ORCID: https://orcid.org/0000-0002-2293-9743)
- Carl‐Mikael Suomivuori (ORCID: https://orcid.org/0000-0002-2445-8791)
- Suhyang Kim (ORCID: https://orcid.org/0000-0002-2817-1202)
- Atsushi Fukunaga (ORCID: https://orcid.org/0000-0003-2026-8154)
- Ryoji Kise (ORCID: https://orcid.org/0009-0000-6583-1719)
- Junki Koyanagi
- Ron O. Dror (ORCID: https://orcid.org/0000-0002-6418-2793)
- Masaki Tsujimura (ORCID: https://orcid.org/0000-0002-7554-7372)
- Asuka Inoue (ORCID: https://orcid.org/0000-0003-0805-4049)
- Kazuhiro Kobayashi (ORCID: https://orcid.org/0000-0002-3366-3586)
- Hiroshi Ishikita (ORCID: https://orcid.org/0000-0002-5849-8150)
- Kouki Kawakami (ORCID: https://orcid.org/0000-0002-2507-8619)
- Keitaro Yamashita (ORCID: https://orcid.org/0000-0002-5442-7582)
- Hideaki Kato (ORCID: https://orcid.org/0000-0002-1941-5535)
- Hisako Ikeda
- Mai Kugawa (ORCID: https://orcid.org/0009-0000-9339-9820)
- Wakana J. Inoue
Institutions
- Tokyo University of Science (JP)
- Tokyo University of the Arts (JP)
- Tohoku University (JP)
- Kyoto Pharmaceutical University (JP)
- Japan Science and Technology Agency (JP)
- The University of Tokyo (JP)
- Tohoku Medical and Pharmaceutical University (JP)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-26
- DOI
- https://doi.org/10.1038/s41467-025-57983-4
- Citations
- 8
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Core Research for Evolutional Science and Technology