{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "The Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, 229 Herzl Street, Rehovot76100001, Israel.",
    "The Fritz Haber Center for Molecular Dynamics, The Hebrew University, Jerusalem919041, Israel.",
    "Department of Chemistry and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Max and Anna Webb, Ramat Gan5290002, Israel."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Alon Rainish",
      "orcid": "0009-0001-8117-658X"
    },
    {
      "affs": [
        2
      ],
      "name": "Liel Sapir",
      "orcid": "0000-0001-7652-6541"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Masha Y Niv",
      "orcid": "0000-0001-8275-8795"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/34e7g4tp6v63r.bib",
  "cited_by": 0,
  "doi": "10.1021/acs.jcim.6c00140",
  "fulltext_url": "https://europepmc.org/articles/PMC13625955",
  "id": "34e7g4tp6v63r",
  "issns": [
    "1549-9596",
    "1549-960X"
  ],
  "landing_url": "https://europepmc.org/article/MED/42906028",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W7207771933",
  "pdf_url": "https://europepmc.org/articles/PMC13625955?pdf=render",
  "pmcid": "PMC13625955",
  "pmid": "42906028",
  "published": "2026-09-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/34e7g4tp6v63r.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:57Z",
      "native_id": "MED:42906028",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42906028"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Receptor Mechanisms and Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Dynamics of Ligand Binding Sites and Chloride Penetration in a Bitter Taste GPCR.",
  "title_text": "Dynamics of Ligand Binding Sites and Chloride Penetration in a Bitter Taste GPCR.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:57Z",
  "url": "https://research.draconitic.com/paper/34e7g4tp6v63r",
  "venue": "Journal of chemical information and modeling",
  "versions": []
}