Allosteric rescuing of loss-of-function FFAR2 mutations.
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.
Swaminath
Gayathri
G
Amgen Inc., South San Francisco, CA 94080, USA.
Jaeckel
Peter
P
Guo
Qi
Q
Cardozo
Mario
M
Weiszmann
Jennifer
J
Lindberg
Richard
R
Wang
Yingcai
Y
Schwandner
Ralf
R
Li
Yang
Y
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
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