Bitter taste receptors (TAS2Rs) belong to the GPCR family and are remarkable for their ability to recognize a vast array of structurally unrelated molecules - from secondary plant metabolites to synthetic drugs. The number of TAS2R subtypes varies widely: 3 in chicken, 25 in human, and 50 in frog. We explore how broad chemical sensitivity is achieved at the molecular level.

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We showed that promiscuous ligands (those that activate many TAS2Rs) tend to be larger, more hydrophobic, and more flexible. In contrast, narrowly tuned TAS2Rs have smaller and less hydrophobic binding cavities than promiscuous TAS2Rs. [Promiscuity and selectivity of bitter molecules and their receptors]

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The most promiscuous TAS2R is human TAS2R14, which is activated by many diverse molecules but inhibited by only a few. Using an iterative computational and experimental approach, we discovered novel antagonists, described in Discovery of TAS2R14 bitter taste receptor antagonists using iterative computational and functional approaches. These antagonists are now used as chemical probes.

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To understand the atomistic details that underlie this promiscuity, we collaborated to solve the CryoEM structure. Our paper Cryo-EM structure of the bitter taste receptor TAS2R14 with agonists and antagonists reveals two binding sites showed that agonists can bind both at the canonical extracellular site and at a novel intracellular binding site. In the figure below, Flufenamic acid, a well-studied TAS2R14 agonist, is bound in both binding sites.