{
  "abstract": "We report the first instance in a class B1 G protein-coupled receptor (GPCR) of a charged residue that exchanges one state-specific salt bridge for another, and the first evidence that this arrangement recurs at non-homologous positions in two receptor classes. In the human glucagon-like peptide-1 receptor (GLP-1R), E408, generic number 8.49x49, pairs with R348 (6.37x37) in 5 of 5 scorable inactive structures and 0 of 52 active, and with R176 (2.46x46) in 42 of 52 active structures and 0 of 6 inactive. Across all fifteen class B1 receptors, the bond to 6.37x37 is absent from all 131 scorable active structures and the bond to 2.46x46 is present in 97 of 135, so the active-state arrangement holds family-wide; the exchange requires both states, and only GLP-1R carries enough inactive structures to show it. These three positions, together with a fourth at 8.47x47, have been described as a cytoplasmic polar network that holds the receptor inactive and breaks on activation, releasing its residues, a reading carried from homology models and mutagenesis through the first activated structure of the receptor to ligand-free G protein complexes of three class B1 receptors in 2024 and to a clinical report in the parathyroid hormone receptor in 2026 [1-7]. Release predicts that the pivot ends the transition bound to fewer partners. It does not: the number of salt bridges it makes does not change across the transition, only the identity of its partner. The inactive-state bond does break, as reported. The pivot is not released: it takes a second partner that is carried only in the active state. We name this arrangement an ionic router. An ionic router is a charged residue that exchanges salt-bridge partners between two conformational states: in each state it binds at least one oppositely charged partner that it does not bind in the other. Each arm is itself a lock, and the two are mutually exclusive: one is closed in each state, so the pivot is never free. The arrangement was found by an unbiased screen that ranked 2,257 charged positions across 61 receptors, scored only on the separation between partner-identity change and partner-count change. No measure of this form is reported in the literature, and a measure that scores one contact at a time cannot separate an exchange from a loss. The screen places the GLP-1R position first of 48 rankable positions in that receptor. Without reference to that result, it places the equivalent class A arrangement first of 38 rankable charged positions in bovine rhodopsin, recovering the exchange at E247 (6.30x30) between R135 (3.50x50) and K231 (5.66x66), partners that never contact one another in any structure. Prior reports describe the class A exchange from the ligand-free opsin structures, from NMR and from simulation [8-12], and propose an equivalent contact in the adenosine receptors from simulation [13, 14]. Recovering a documented arrangement without being directed at it is the control on the measure, and the measure then finds the class B1 instance at positions already described, where it reverses the direction assigned to them. It is the first such arrangement reported outside class A. The class A pairing could not have been used in GLP-1R: all fifteen class B1 receptors carry a glutamate where class A carries the arginine at 3.50x50, and that position is occupied instead by a histidine contact present in both states. A single side chain that registers activation state by which partner it holds is a candidate site for precision drug design and for understanding the molecular basis of disease.",
  "abstract_shown": true,
  "affiliations": [
    "Deep EigenMatics, Inc."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Stephen G. Odaibo",
      "orcid": "0000-0001-9777-312X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/6bbegjh88jzbm.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010893/v1",
  "fulltext_url": null,
  "id": "6bbegjh88jzbm",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010893/v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W7223175191",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-22",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/6bbegjh88jzbm.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:26Z",
      "native_id": "10.26434/chemrxiv.15010893",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010893/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Receptor Mechanisms and Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Ionic router: a shared acidic pivot swaps one salt bridge for another, encoding activation state at non-homologous positions in class B1 and class A GPCRs",
  "title_text": "Ionic router: a shared acidic pivot swaps one salt bridge for another, encoding activation state at non-homologous positions in class B1 and class A GPCRs",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:26Z",
  "url": "https://research.draconitic.com/paper/6bbegjh88jzbm",
  "venue": "ChemRxiv",
  "versions": []
}