Structural insights into lipid chain-length selectivity and allosteric regulation of FFA2

Mai Kugawa, Kouki Kawakami, Ryoji Kise, Carl-Mikael Suomivuori, Masaki Tsujimura, Kazuhiro Kobayashi, Asato Kojima, Wakana J. Inoue, Masahiro Fukuda, Toshiki E. Matsui, Ayami Fukunaga, Junki Koyanagi, Suhyang Kim, Hisako Ikeda, Keitaro Yamashita, Keisuke Saito, Hiroshi Ishikita, Ron O. Dror, Asuka Inoue () and Hideaki E. Kato ()
Additional contact information
Mai Kugawa: The University of Tokyo
Kouki Kawakami: The University of Tokyo
Ryoji Kise: Tohoku University
Carl-Mikael Suomivuori: Stanford University
Masaki Tsujimura: The University of Tokyo
Kazuhiro Kobayashi: The University of Tokyo
Asato Kojima: The University of Tokyo
Wakana J. Inoue: The University of Tokyo
Masahiro Fukuda: The University of Tokyo
Toshiki E. Matsui: The University of Tokyo
Ayami Fukunaga: The University of Tokyo
Junki Koyanagi: The University of Tokyo
Suhyang Kim: The University of Tokyo
Hisako Ikeda: The University of Tokyo
Keitaro Yamashita: The University of Tokyo
Keisuke Saito: The University of Tokyo
Hiroshi Ishikita: The University of Tokyo
Ron O. Dror: Stanford University
Asuka Inoue: Tohoku University
Hideaki E. Kato: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57983-4

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