title: Allosteric rescuing of loss-of-function FFAR2 mutations.
abstract: FFAR2 (GPR43) is a receptor for short-chain fatty acids (SCFAs), acetate and propionate. In the current study, we investigate the molecular determinants contributing to receptor activation by endogenous ligands. Mutational analysis revealed several important residues located in transmembrane domains (TM) 3, 4, 5, 6, and 7 for acetate binding. Interestingly, mutations that abolished acetate activity, including the mutation in the well-conserved D(E)RY motif, could be rescued by a recently identified synthetic allosteric agonist. These findings provide additional insight into agonist binding and activation which may aid in designing allosteric ligands for targeting receptor function in various diseases.
authors.affiliation: Amgen Inc., South San Francisco, CA 94080, USA.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Swaminath
authors.forename: Peter
authors.initials: P
authors.lastname: Jaeckel
authors.forename: Qi
authors.initials: Q
authors.lastname: Guo
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Jennifer
authors.initials: J
authors.lastname: Weiszmann
authors.forename: Richard
authors.initials: R
authors.lastname: Lindberg
authors.forename: Yingcai
authors.initials: Y
authors.lastname: Wang
authors.forename: Ralf
authors.initials: R
authors.lastname: Schwandner
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D019342:Acetic Acid / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site / Q000235:genetics; D020816:Amino Acid Motifs; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled
chemical_list: D000081:Acetamides; D019342:Acetic Acid; D008024:Ligands; D050505:Mutant Proteins; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C473103:FFAR2 protein, human; D043562:Receptors, G-Protein-Coupled