Allosteric rescuing of loss-of-function FFAR2 mutations |
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Authors: | Gayathri Swaminath Peter Jaeckel Qi Guo Jennifer Weiszmann Yingcai Wang Yang Li |
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Affiliation: | a Amgen Inc., 1120 Veterans Blvd., South San Francisco, CA 94080, United States b Amgen Research-GMBH, Regensburg, Germany |
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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. |
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Keywords: | Free fatty acid receptor 2 FFA2 GPR43 Allosteric agonist Short-chain fatty acids AMG7703 |
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