Conserved residues control the T1R3-specific allosteric signaling pathway of the mammalian sweet taste receptor.

Conserved residues control the T1R3-specific allosteric signaling pathway of the mammalian sweet taste receptor.
Chem Senses. 2019 Mar 20;:
Authors: Chéron JB, Soohoo A, Wang Y, Golebiowski J, Antonczak S, Jiang P, Fiorucci S
Abstract
Mammalian sensory systems detect sweet taste through the activation of a single heteromeric T1R2/T1R3 receptor belonging to class C G-protein-coupled receptors. Allosteric ligands are known to interact within the transmembrane domain, yet a complete view of receptor activation remains elusive. By combining site-directed mutagenesis with computational modeling, we investigate the structure and dynamics of the allosteric binding pocket of the T1R3 sweet taste receptor in its apo form, and in the presence of an allosteric ligand, cyclamate. A novel positively-charged residue at the extracellular loop 2 is shown to interact with the ligand. Molecular dynamics simulations capture significant differences in the behavior of a network of conserved residues with and without cyclamate, although they do not directly interact with the allosteric ligand. Structural models show that they adopt alternate conformations, associated with a conformational change in the transmembrane region. Site-directed mutagenesis confirms that these residues are unequivocally involved in the receptor function and the allosteric signaling mechanism of the sweet taste receptor. Similar to a large portion of the transmembrane domain, the...

Source: Chemical Senses - March 19, 2019 Category: Biochemistry Authors: Chéron JB, Soohoo A, Wang Y, Golebiowski J, Antonczak S, Jiang P, Fiorucci S Tags: Chem Senses Source Type: research