Activation and allosteric modulation of free fatty acid receptors (FFAs)

Abstract ID 129266 Poster Board 165 Free fatty acid receptors (FFARs) constitute a group of lipid G protein-coupled receptors (GPCRs) that respond to long-chain fatty acids (LCFAs) including DHA and EPA and short-chain fatty acids (SCFAs) including butyrate and acetate generated by the intestine microbiota. Agonists of this group of GPCRs hold the promise of becoming new drugs for treating diabetes and other inflammatory diseases. We present cryo-EM structures of members of this family including FFA1, FFA2, and FFA4. Combined with mutagenesis and computational simulations studies, our structures reveal the molecular mechanisms underlying ligand selectivity, biased signaling, and activation of FFARs. In particular, we reveal the molecular details of diverse allosteric sites in FFA2 for distinct allosteric modulators and non-canonical receptor activation mechanisms. We expect that our results will facilitate the development of novel modulators of FFARs for a variety of inflammatory diseases.