ArticleNature communications2025
Structural insights into lipid chain-length selectivity and allosteric regulation of FFA2.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- Short-chain fatty acid-producing commensals: Key modulators of AD neuroinflammation via the microbiota-gut-brain axis.Current research in microbial sciences · 2026Review
- Universal pipeline for high-resolution GPCR structure determination.Nature structural & molecular biology · 2026Article
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- Article
- Optimized bacterial expression of a synthetic BRIL antibody.Acta crystallographica. Section F, Structural biology communications · 2026Article
- Free fatty acid receptor 2 allosterism is defined by cellular context.Cell communication and signaling : CCS · 2026Article
- Fatty Acid-Sensing G Protein-Coupled Receptors in Skeletal Metabolism.Journal of bone metabolism · 2026Article
- The gut microbiota-short-chain fatty acid-inflammation axis in Parkinson's disease motor dysfunction: mechanisms and future of dietary interventions.Frontiers in neurology · 2026Review
- Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation.Frontiers in immunology · 2026Review
- GPR43 deficiency aggravates sepsis by promoting gut microbiota-dependent barrier disruption and HIF-1α-ENO1 axis-mediated M1 polarization of macrophages.Cellular & molecular biology letters · 2025Article
- Molecular insights into ligand recognition and signaling of OXGR1.Nature communications · 2025Article
- Review
Corrections and comments
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Authors and funding
20 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.