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bioRxiv · 10.64898/2026.05.14.725165

Structural Basis of Ligand-Specific Orthosteric-Allosteric Coupling and Sensory Tuning in the Human Bitter Taste Receptor TAS2R14

Zhou, T.·Wang, J.·Wang, C.·Han, Z.·Zhang, Y.·Ouyang, Z.·Ye, S.·Wu, S.·Qiao, A.
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Abstract

The bitter taste receptor TAS2R14 recognizes hundreds of structurally diverse ligands, yet the mechanisms governing its broad promiscuity, graded agonist efficacy, and multi-site regulation remain unclear. Here, we report cryo-EM structures of TAS2R14-Gi1 complexes bound to 3,5-diiodosalicylic acid (DA), flufenamic acid (FA) and aristolochic acid (AA) at resolutions of 2.44 [A], 2.39 [A], and 2.69 [A], with a clear efficacy hierarchy of AA > FA > DA. Transmembrane helix 6 (TM6) acts as a core regulatory hub, with agonist binding triggering 12 [A] lever-like TM6 rearrangements to reshape receptor interfaces and modulate G-protein coupling strength. We also identify cholesterol hemisuccinate (CHS) as a new TAS2R14 orthosteric agonist, selectively potentiating DA-mediated signaling potency by [~]5-fold via allosteric-orthosteric coupling without affecting FA or AA. Our findings show TM6 dynamics unify TAS2R14s key functional features, advancing insights into bitter receptor activation and sterol regulation.

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Zhou, T., Wang, J., Wang, C., Han, Z., Zhang, Y., Ouyang, Z., Ye, S., Wu, S., Qiao, A.. 2026-05-17. Structural Basis of Ligand-Specific Orthosteric-Allosteric Coupling and Sensory Tuning in the Human Bitter Taste Receptor TAS2R14. https://doi.org/10.64898/2026.05.14.725165

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