{
  "abstract": "Ion permeation in the two-pore-domain K+ (K2P) channel TREK1 is gated largely at the selectivity filter (SF), by a C-type-like inactivation mechanism involving distortions of the SF structure; and by a carbonyl flip, which disrupts K+ coordination. Both are prevented by a small-molecule activator bound adjacent to the SF, in a site termed the modulator pocket; yet which pocket regions carry the binding signal, and whether they couple to gating, is unclear. We use 46 chemical substitutions on the activator ML335, evaluated by non-equilibrium alchemical free-energy calculations, as an affinity perturbation scan on the lower- and upper pocket. The response is strongly asymmetric: Lower-ring substitutions impair binding, which we trace to a {pi}-{pi} stacking network connecting the M3, P2, P1 helices, and the SF. Conversely, upper-ring substitutions are tolerated and reshape contacts with the Cap-P1 and SF2-M4 loops; and with the upper SF. The identified affinity hotspots overlap with residues independently implicated in TREK gating by external cues such as pH, temperature, pressure, and cytosolic-sensor transduction, suggesting that high-affinity pocket sites might also shape the gating landscape.",
  "abstract_shown": true,
  "affiliations": [
    "Max Planck Institute for multidisciplinary science"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "name": "E. Mendez-Otalvaro"
    },
    {
      "affs": [
        0
      ],
      "name": "B. de Groot"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/065ns61ttm39z.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.13.758835",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.13.758835v1.full",
  "id": "065ns61ttm39z",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.13.758835v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7221835278",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.13.758835v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-13",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/065ns61ttm39z.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:27:47Z",
      "native_id": "10.64898/2026.10.13.758835",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.13.758835v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "A chemical perturbation scan on a K2P channel modulator pocket identifies affinity hotspots",
  "title_text": "A chemical perturbation scan on a K2P channel modulator pocket identifies affinity hotspots",
  "type": "preprint",
  "updated_at": "2026-10-30T12:27:47Z",
  "url": "https://research.draconitic.com/paper/065ns61ttm39z",
  "venue": "bioRxiv",
  "versions": []
}