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TitleStructural insights into lipid chain-length selectivity and allosteric regulation of FFA2.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 2809, Year 2025
Publish dateMar 26, 2025
AuthorsMai 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 / Hideaki E Kato /
PubMed AbstractThe 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 ...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.
External linksNat Commun / PubMed:40140663 / PubMed Central
MethodsEM (single particle)
Resolution3.19 - 3.36 Å
Structure data

39003

8y6w

EMDB-39003, PDB-8y6w:
TUG-1375 and 4-CMTB-bound human FFA2 in complex with Gi
Method: EM (single particle) / Resolution: 3.19 Å

39004

8y6y

EMDB-39004, PDB-8y6y:
GLPG0974-bound human FFA2
Method: EM (single particle) / Resolution: 3.36 Å

Chemicals

ChemComp-9UJ:
(2R,4R)-2-(2-chlorophenyl)-3-[4-(3,5-dimethyl-1,2-oxazol-4-yl)phenyl]carbonyl-1,3-thiazolidine-4-carboxylic acid

PDB-1lyc:
The impact of the physical and chemical enviroment on the molecular structure of Coprinus cinereus peroxidase

PDB-1lyd:
CRYSTAL STRUCTURE OF T4-LYSOZYME GENERATED FROM SYNTHETIC CODING DNA EXPRESSED IN ESCHERICHIA COLI

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR

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