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The Trace Amine Associated Receptors (TAARs) are a family of chemosensory receptors that recognize volatile amines. These receptors are few in number and highly conserved, compared to regular olfactory receptors. Polymorphisms in the TAAR family can have a drastic impact on our perception of amine compounds. Our study combine numerical simulations with in vitro experiments to reveal the activation mechanisms of the human TAAR5 receptor. The study focused on the hTAAR5-S95P polymorphism, which is found at high frequency in Nordic countries. This mutation affects the perception of trimethylamine (TMA), making individuals less able to perceive the smell of rotten fish caused by this molecule. The study's 3D model captures the inability of the hTAAR5-S95P variant to be activated by TMA in vitro, as well as the activation of the receptor by different agonists. Long-scale molecular dynamics simulations were used to study the system bound to ligands with different efficacies, providing insight into the features of a prototypical active state of G protein-coupled receptors. The study has identified two specific features of the TAAR family that are responsible for the altered perception of TMA in individuals with this polymorphism.

Understanding how chemicals code for a certain type of taste is fundamental for the development of a rational method to create new taste modulators. The identification of these new candidates is important for the food industry and would also be beneficial for the pharmacology industry. In humans, the bitter taste depends on a large family of 25 taste receptors type 2 (TAS2Rs) belonging to the G protein-coupled receptor (GPCR) family. They are classified distantly related to class A GPCR and, to date, the experimental structures have not been determined for any TAS2Rs. Here we present a new structure-based virtual screening strategy to expand the chemical space of bitter taste receptors. Combining molecular modeling (based on a recent general approach for modeling all mammal TAS2Rs1) and in vitro functional assays, we identified new active compounds as activators of human TAS2R14. Such agonists will be of broad interest beyond food science since TAS2Rs are ectopically expressed in other parts of the human body besides the tongue.