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Conserved Residues Control the T1R3-Specific Allosteric Signaling Pathway of the Mammalian Sweet-Taste Receptor

Title
Conserved Residues Control the T1R3-Specific Allosteric Signaling Pathway of the Mammalian Sweet-Taste Receptor
Authors
Cheron, Jean-BaptisteSoohoo, AmandaWang, YiGolebiowski, JeromeAntonczak, SergeJiang, PeihuaFiorucci, Sebastien
Issue Date
2019-06
Citation
Chemical Senses, 44(5), 303-310
Type
Article
Article Type
Article
Author Keywords
allosteric binding siteclass C GPCRcyclamatemammaliansweet-taste receptortaste modulator
Keywords
ACTIVATION MECHANISMHEPTAHELICAL DOMAINMOLECULAR-MECHANISMMODULATIONSERVERT1R3
ISSN
0379-864X
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, they are highly conserved among mammals, suggesting an activation mechanism that is evolutionarily conserved. This work provides a structural basis for describing the dynamics of the receptor, and for the rational design of new sweet-taste modulators. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
URI
http://hdl.handle.net/20.500.11750/10620
DOI
10.1093/chemse/bjz015
Publisher
Oxford University Press
Files:
There are no files associated with this item.
Collection:
ETC1. Journal Articles


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