TY - JOUR
T1 - Prediction of dynamic allostery for the transmembrane domain of the sweet taste receptor subunit, TAS1R3
AU - Sanematsu, Keisuke
AU - Yamamoto, Masato
AU - Nagasato, Yuki
AU - Kawabata, Yuko
AU - Watanabe, Yu
AU - Iwata, Shusuke
AU - Takai, Shingo
AU - Toko, Kiyoshi
AU - Matsui, Toshiro
AU - Wada, Naohisa
AU - Shigemura, Noriatsu
N1 - Funding Information:
The computation was carried out using the computer resources offered under the category of General Projects by the Research Institute for Information Technology, Kyushu University. We thank Dr. Makoto Tominaga (National Institutes of Natural Sciences, Japan) for providing HEK293 cells. This work was supported in whole or part by JSPS KAKENHI grant numbers JP21H05006 (to K.T.), JP19H03818 (to N.S.), JP18K09523 (to K.S.) and JP21K09818 (to K.S.).
Funding Information:
The computation was carried out using the computer resources offered under the category of General Projects by the Research Institute for Information Technology, Kyushu University. We thank Dr. Makoto Tominaga (National Institutes of Natural Sciences, Japan) for providing HEK293 cells. This work was supported in whole or part by JSPS KAKENHI grant numbers JP21H05006 (to K.T.), JP19H03818 (to N.S.), JP18K09523 (to K.S.) and JP21K09818 (to K.S.).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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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U2 - 10.1038/s42003-023-04705-5
DO - 10.1038/s42003-023-04705-5
M3 - Article
C2 - 37012338
AN - SCOPUS:85151756577
SN - 2399-3642
VL - 6
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 340
ER -