Integrative structural modeling reveals functional molecular switches of human G protein-coupled bittertaste receptors

Abstract

On the human tongue, the bitter taste depends on a large family of 25 taste receptors type 2 (TAS2R) belonging to the G protein-coupled receptor (GPCR) family and classified distantly related to class A GPCR. To date, the experimental structures have not been determined for any TAS2R and key residues controlling their function are still under debate. Here we streamline the modeling of these receptors using an integrative approach combining sequence analysis, molecular modeling and site-directed mutagenesis followed by functional assays. We provide a general approach for modeling all mammal TAS2R and identify functional motifs or residues which are central to understand how we perceive bitterness. Above the protocol which is transposable to all TAS2R, the identification of functional molecular switches lays the groundwork for the rational design of chemical modulators of bitter taste receptors. Such ligands will be of broad interest beyond food science since bitter-taste receptors are ectopically expressed in other parts of the human body besides the tongue. Topin et al. Functional molecular switches of mammalian G protein-coupled bitter-taste receptors. Cell. Mol. Life Sci., 2021, 78, 7605-7615. Funding Acknowledgments: This work was supported by the French Ministry of Higher Education and Research [PhD Fellowship], by GIRACT (Geneva, Switzerland) [9th European PhD in Flavor Research Bursaries for first year students] and the Gen Foundation (Registered UK Charity No. 1071026) [a charitable trust which principally provides grants to students/researchers in natural sciences, in particular food sciences/technology]. This work has also been supported by the French government, through the UCAJEDI Investments in the Future project managed by the National Research Agency (ANR) with the reference number ANR15-IDEX-01. The authors are grateful to the OPAL infrastructure from Universite Cote drAzur and the Universite Cote drAzurrs Center for High-Performance Computing for providing resources and support. FCOI Declarations: None