Our sense of taste is critical for evaluating which substances are good to eat, and its importance is recognised in the many metaphors that surround the four tastes traditionally recognised in the West: a sweet melody, the souring of a relationship, bitter enemies, and salt of the earth. In 1908, a Japanese scientist, Kikunae Ikeda, recognised a fifth taste which he called umami, meaning “deliciousness”. Umami is a pleasant savoury taste that results from the detection of glutamic acid or glutamates which occur in protein-rich foods such as meat, cheese, and seafood. A truncated form of the metabotropic glutamate receptor, mGluR4 (taste mGluR4), and a heterodimeric (T1R1/T1R3) taste receptor complex have both been linked to the sensation of umami.
The umami taste triggered by L-glutamate is known to be dramatically enhanced by 5’ ribonucleotides, such as 5′-inosine monophosphate and guanosine 5′-monophosphate, and a new study describes the mechanism underlying this synergy. Scientists from Senomyx and BioPredict used chimeric T1R receptors, site-directed mutagenesis and molecular modelling to devise a cooperative ligand-binding model in which L-glutamate binds close to the hinge region of the ‘Venus flytrap’ (VFT) domain of T1R1, and the 5′ ribonucleotide binds to an adjacent site to further stabilize the closed conformation.
Allosteric modulators are attractive as drug candidates, especially since these might be expected to afford greater subtype selectivity in the case of closely related receptors that share the same ligand, such as mGluRs. Positive allosteric modulators, which have an effect only when the natural ligand is present in vivo, also have the potential to reduce side effects that could occur with constitutively active agonists. Identification of the L-glutamate and 5′-inosine monophosphate binding sites on the VFT domain of T1R1 may facilitate the development of allosteric modulators of other family C GPCRs as well as the development of new flavour enhancers.
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