Prediction of dynamic allostery for the transmembrane domain of the sweet taste receptor subunit, TAS1R3

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  • Sanematsu, Keisuke
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University Oral Health/Brain Health/Total Health Research Center, Graduate School of Dental Science, Kyushu University Research and Development Center for Five-Sense Devices, Kyushu University
  • Yamamoto, Masato
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University Department of General Dentistry, Division of Interdisciplinary Dentistry, Faculty of Dental Science, Kyushu University
  • Nagasato, Yuki
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University Department of Bioresources and Biosciences, Faculty of Agriculture, Graduate School of Kyushu University
  • Kawabata, Yuko
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University
  • Watanabe, Yu
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University
  • Iwata, Shusuke
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University Research and Development Center for Five-Sense Devices, Kyushu University
  • Takai, Shingo
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University
  • Toko, Kiyoshi
    Research and Development Center for Five-Sense Devices, Kyushu University Institute for Advanced Study, Kyushu University
  • Matsui, Toshiro
    Research and Development Center for Five-Sense Devices, Kyushu University Department of Bioresources and Biosciences, Faculty of Agriculture, Graduate School of Kyushu University
  • Wada, Naohisa
    Department of General Dentistry, Division of Interdisciplinary Dentistry, Faculty of Dental Science, Kyushu University
  • Shigemura, Noriatsu
    Section of Oral Neuroscience, Graduate School of Dental Science, Kyushu University Research and Development Center for Five-Sense Devices, Kyushu University

Description

The sweet taste receptor plays an essential role as an energy sensor by detecting carbohydrates. However, the dynamic mechanisms of receptor activation remain unclear. Here, we describe the interactions between the transmembrane domain of the G protein-coupled sweet receptor subunit, TAS1R3, and allosteric modulators. Molecular dynamics simulations reproduced species-specific sensitivity to ligands. We found that a human-specific sweetener, cyclamate, interacted with the mouse receptor as a negative allosteric modulator. Agonist-induced allostery during receptor activation was found to destabilize the intracellular part of the receptor, which potentially interfaces with the Gα subunit, through ionic lock opening. A common human variant (R757C) of the TAS1R3 exhibited a reduced response to sweet taste, in support of our predictions. Furthermore, histidine residues in the binding site acted as pH-sensitive microswitches to modulate the sensitivity to saccharin. This study provides important insights that may facilitate the prediction of dynamic activation mechanisms for other G protein-coupled receptors.

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