{
  "abstract": "PKD2 (TRPP1) is a TRPP ion channel whose dysfunction causes autosomal dominant polycystic kidney disease (ADPKD). Understanding its conformational states and gating mechanism is important for elucidating its function and for structure-based drug discovery. Cryo-EM structures of WT-PKD2 contain a local {pi}-helical turn in the S6 pore-lining helix ({pi}-conformation). In contrast, a fully -helical S6 (-conformation) was observed in the gain-of-function mutant F604P-PKD2 and interpreted as the open state, leading to the proposed {pi}-to- activation mechanism. However, whether the -conformation can support function has never been directly established. Here, using molecular dynamics simulations, we investigate the functional properties of the -and {pi}-conformations of PKD2. The -conformation remains dewetted unless the lower gate is widened beyond the conformational range observed in mammalian TRP channels. By contrast, the {pi}-conformation supports pore hydration and ion conduction following a small opening of the L677 gate, with simulated conductance comparable to experimental measurements. The closely related PKD2L1 (TRPP2) channel shows a similar dependence on conformation, with a hydrated {pi}-conformation and a dewetted -conformation. Together, these findings challenge the assignment of the -conformation as the conductive state and support a model in which the {pi}-conformation represents the functionally relevant state of TRPP channels. This model suggests that activation may involve an -to-{pi} transition rather than the previously proposed {pi}-to- transition, providing a new framework for understanding TRPP channel gating. This work sheds light on the molecular basis of polycystin channel dysfunction and could facilitate the development of PKD2-targeted therapeutic strategies for ADPKD.",
  "abstract_shown": true,
  "affiliations": [
    "University of Edinburgh"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "C. Zhang"
    },
    {
      "name": "W. Kopec"
    },
    {
      "affs": [
        0
      ],
      "name": "J. Michel"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8rndfad0bt9gr.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.04.764271",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764271v1.full",
  "id": "8rndfad0bt9gr",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764271v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764271v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/8rndfad0bt9gr.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T00:22:14Z",
      "native_id": "10.64898/2026.11.04.764271",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764271v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "TRPP Ion Channels Function in the π-Conformation Rather Than the α-Conformation",
  "title_text": "TRPP Ion Channels Function in the π-Conformation Rather Than the α-Conformation",
  "type": "preprint",
  "updated_at": "2026-11-07T00:20:59Z",
  "url": "https://research.draconitic.com/paper/8rndfad0bt9gr",
  "venue": "bioRxiv",
  "versions": []
}