Dynamics of Ligand Binding Sites and Chloride Penetration in a Bitter Taste GPCR.
- 1The Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, 229 Herzl Street, Rehovot76100001, Israel.
- 2The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem919041, Israel.
- 3Department of Chemistry and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Max and Anna Webb, Ramat Gan5290002, Israel.
Abstract
Taste perception strongly influences food choice, drug compliance, and dietary behavior. Bitter taste receptors belong to a subfamily of Family A GPCRs, while having unique features and deviations from conserved motifs. Recent cryo-EM structures revealed that the human bitter taste receptor TAS2R14 contains not only the canonical extracellular binding site, but also a novel intracellular site, raising questions about their interplay. Here, we performed all-atom molecular dynamics simulations of TAS2R14 in an explicit membrane to probe different receptor states: both cholesterol (extracellular) and aristolochic acid (intracellular) bound, only cholesterol bound, only aristolochic acid bound, and the apo receptor, with and without the G protein. Ligand occupancy at either site reshaped the volume, hydration, and conformational plasticity of both pockets and modulated the relative proximity of transmembrane helices 3 and 6. In simulations lacking the intracellular agonist but containing cholesterol, we observed intracellular entry of chloride ions and their long-lived interaction with the TAS2R-conserved R55 (BW position 2.50), revealing a charge-inverted interaction relative to the D2.50-sodium interaction described in many class A GPCRs. Apo simulations without G protein showed shorter-lived chloride visits to the same region. Together, these findings point to the intracellular pocket as a promising target for future mechanistic and ligand-design studies on bitter taste GPCRs.
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BibTeX
@article{rainish2026dynamics,
title = {{Dynamics of Ligand Binding Sites and Chloride Penetration in a Bitter Taste GPCR.}},
author = {Alon Rainish and Liel Sapir and Masha Y Niv},
journal = {Journal of chemical information and modeling},
year = {2026},
month = sep,
doi = {10.1021/acs.jcim.6c00140},
url = {https://europepmc.org/article/MED/42906028},
note = {CC BY},
}
RIS
TY - JOUR
TI - Dynamics of Ligand Binding Sites and Chloride Penetration in a Bitter Taste GPCR.
AU - Alon Rainish
AU - Liel Sapir
AU - Masha Y Niv
PY - 2026
DA - 2026/09/01
JO - Journal of chemical information and modeling
DO - 10.1021/acs.jcim.6c00140
UR - https://europepmc.org/article/MED/42906028
AB - Taste perception strongly influences food choice, drug compliance, and dietary behavior. Bitter taste receptors belong to a subfamily of Family A GPCRs, while having unique features and deviations from conserved motifs. Recent cryo-EM structures revealed that the human bitter taste receptor TAS2R14 contains not only the canonical extracellular binding site, but also a novel intracellular site, raising questions about their interplay. Here, we performed all-atom molecular dynamics simulations of TAS2R14 in an explicit membrane to probe different receptor states: both cholesterol (extracellular) and aristolochic acid (intracellular) bound, only cholesterol bound, only aristolochic acid bound, and the apo receptor, with and without the G protein. Ligand occupancy at either site reshaped the volume, hydration, and conformational plasticity of both pockets and modulated the relative proximity of transmembrane helices 3 and 6. In simulations lacking the intracellular agonist but containing cholesterol, we observed intracellular entry of chloride ions and their long-lived interaction with the TAS2R-conserved R55 (BW position 2.50), revealing a charge-inverted interaction relative to the D2.50-sodium interaction described in many class A GPCRs. Apo simulations without G protein showed shorter-lived chloride visits to the same region. Together, these findings point to the intracellular pocket as a promising target for future mechanistic and ligand-design studies on bitter taste GPCRs.
SN - 1549-9596
SN - 1549-960X
ER -