Biophysical Society Thematic Meeting | Bucharest 2026

Biophysics of Membrane Reactions in Brian

Thursday Speaker Abstracts

HIDDEN POCKETS AND INTRACELLULAR IONS: LESSONS FROM BITTER TASTE GPCRS Masha Niv The Hebrew University of Jerusalem, The Institute of Biochemistry, Food and Nutrition, Rehovot, Israel Taste GPCRs are best known for their role on the tongue, where they influence food choice and consumption. Yet, their extraoral expression in tissues such as the gut, heart, and brain suggests additional physiological roles and the existence of unknown endogenous ligands. Bitter taste receptors, in particular, recognize hundreds of chemically diverse ligands, which we curate in the BitterDB database. To illuminate the chemical and biological spaces of taste GPCR signaling, we integrate AI-driven modeling with experimental testing. Models predicting bitterness, combined with receptor–ligand docking and iterative data-driven refinement, led to the discovery of antagonists for the most promiscuous and widely expressed bitter taste receptor subtype in human, TAS2R14. Unexpectedly, CryoEM structures of TAS2R14 from our and other labs revealed an intracellular ligand-binding pocket. Site-directed mutagenesis and cell-based functional and recruitment assays showed that the antagonists discovered through docking to the extracellular (canonical) pocket of the receptor 3D models, interact mainly with the novel intracellular pocket. Molecular dynamics simulations of the apo, holo, and single-site complexes showed chloride ion entry from the intracellular side, suggesting an interesting inverted mechanism compared to Family A GPCRs, for which sodium entry from the extracellular region was previously shown.I will conclude by presenting computational strategies for assigning ligands to “unseen” bitter receptors, explicitly considering both canonical and intracellular binding sites, and discuss implications for GPCR conformational dynamics and function. References: Margulis et al., BitterMatch: recommendation systems for matching molecules with bitter taste receptors. J Cheminform (2022); Fierro et al., Inhibiting a promiscuous GPCR: iterative discovery of bitter taste receptor ligands Cell Mol Life Sci (2023); Peri et al., A bitter anti-inflammatory drug binds at two distinct sites of a human bitter taste GPCR. Nat Commun (2024).

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