Unknown

Dataset Information

0

Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator.


ABSTRACT: Allosteric agonists are powerful tools for exploring the pharmacology of closely related G protein-coupled receptors that have nonselective endogenous ligands, such as the short chain fatty acids at free fatty acid receptors 2 and 3 (FFA2/GPR43 and FFA3/GPR41, respectively). We explored the molecular mechanisms mediating the activity of 4-chloro-?-(1-methylethyl)-N-2-thiazolylbenzeneacetamide (4-CMTB), a recently described phenylacetamide allosteric agonist and allosteric modulator of endogenous ligand function at human FFA2, by combining our previous knowledge of the orthosteric binding site with targeted examination of 4-CMTB structure-activity relationships and mutagenesis and chimeric receptor generation. Here we show that 4-CMTB is a selective agonist for FFA2 that binds to a site distinct from the orthosteric site of the receptor. Ligand structure-activity relationship studies indicated that the N-thiazolyl amide is likely to provide hydrogen bond donor/acceptor interactions with the receptor. Substitution at Leu(173) or the exchange of the entire extracellular loop 2 of FFA2 with that of FFA3 was sufficient to reduce or ablate, respectively, allosteric communication between the endogenous and allosteric agonists. Thus, we conclude that extracellular loop 2 of human FFA2 is required for transduction of cooperative signaling between the orthosteric and an as-yet-undefined allosteric binding site of the FFA2 receptor that is occupied by 4-CMTB.

PROVIDER: S-EPMC3127537 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

| S-EPMC4492757 | BioStudies
| S-EPMC7536384 | BioStudies
| S-EPMC3060514 | BioStudies
| S-EPMC4561419 | BioStudies
| S-EPMC6282569 | BioStudies
| S-EPMC6071421 | BioStudies
| S-EPMC3850046 | BioStudies
| S-EPMC3913357 | BioStudies
2010-01-01 | S-EPMC2936488 | BioStudies
| S-EPMC2844194 | BioStudies