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

Keisuke Sanematsu, Masato Yamamoto, Yuki Nagasato, Yuko Kawabata, Yu Watanabe, Shusuke Iwata, Shingo Takai, Kiyoshi Toko, Toshiro Matsui, Naohisa Wada, Noriatsu Shigemura

研究成果: ジャーナルへの寄稿学術誌査読

1 被引用数 (Scopus)

抄録

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.

本文言語英語
論文番号340
ジャーナルCommunications Biology
6
1
DOI
出版ステータス出版済み - 12月 2023

!!!All Science Journal Classification (ASJC) codes

  • 医学(その他)
  • 生化学、遺伝学、分子生物学(全般)
  • 農業および生物科学(全般)

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