{
  "abstract": "Selective pharmacological control of gap junction communication remains challenging because existing small-molecule connexin inhibitors act across multiple isoforms. The structural basis of this broad activity remains incompletely understood. Here, we used single-particle cryo-electron microscopy to examine native connexin-46/50 gap junction channels treated with two commonly used and chemically distinct inhibitors, 2-aminoethoxydiphenyl borate (2-APB) and carbenoxolone (CBX). Both treatments perturb the hydrophobic N-terminal (NT)-docking groove, but produce distinct conformational ensembles. 2-APB yields ordered destabilized-open and gated NT states resembling conformations observed during physiological pH- and Ca2+-dependent gating, with ligand- and lipid-associated densities accompanying the gated state. In contrast, CBX-compatible density occupies the same groove and is associated with loss of an ordered NT conformation, consistent with steric competition and altered physicochemical complementarity at the NT-docking site. Comparison with inhibitor-treated connexin-32 and connexin-36 structures identifies this region as a structurally conserved, pharmacologically sensitive pocket. These findings reveal how chemically diverse inhibitors perturb a conserved element of the native gating machinery while producing divergent NT-gating ensembles, providing a structural rationale for broad cross-isoform activity and identifying sequence-variable pocket margins that may support more selective modulation.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "Joshua M. Jarodsky"
    },
    {
      "name": "Janette B. Myers"
    },
    {
      "name": "Steve L. Reichow",
      "orcid": "0000-0001-5276-7690"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4d7s20hgw57pg.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.26.762086",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.762086v1.full",
  "id": "4d7s20hgw57pg",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.762086v1",
  "language": "en",
  "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"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Connexins and lens biology"
    ]
  ],
  "openalex": "W7223907383",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.26.762086v1.full.pdf",
  "pmcid": "PMC13734007",
  "pmid": "42990440",
  "published": "2026-10-26",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/4d7s20hgw57pg.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:55Z",
      "native_id": "10.64898/2026.10.26.762086",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.26.762086v1"
    },
    {
      "first_seen": "2026-11-08T12:23:40Z",
      "native_id": "PMC13734007",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.26.762086"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Distinct modes of N-terminal remodeling through a conserved inhibitor pocket in connexin-46/50",
  "title_text": "Distinct modes of N-terminal remodeling through a conserved inhibitor pocket in connexin-46/50",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:40Z",
  "url": "https://research.draconitic.com/paper/4d7s20hgw57pg",
  "venue": "bioRxiv",
  "versions": []
}