{
  "abstract": "Receptor activation state is the structural variable that most GPCR drug discovery is implicitly trying to control. Using class A GPCR structures only, we trained the Receptor Class-Activation-Map Localizer (RCL), a classifier that distinguishes active from inactive GPCR structures, and evaluated it on class B1, a family it never saw. Pooled class B1 performance was AUROC 0.9532 (95% CI 0.9201 to 0.9863, n = 146). On GLP-1R, held out entirely, it reached AUROC 1.0000 across 43 structures (37 active, 6 inactive). Attention in GLP-1R concentrates at the cytoplasmic end of TM6, a region also named in the pre-registered specification. Against a permutation null, the intracellular third of that helix is enriched 6.78 to 11.30-fold, against 2.93 to 4.01-fold for the helix taken in full. Within that third a single position dominates. R348, generic number 6.37x37, carries the attention maximum in 42 of 43 GLP-1R structures, active and inactive alike and apo structures included, holding a median of 53.58 times the attention mass a uniform distribution would place on a single residue. The same position carries the maximum in 17 of 18 GCGR and 6 of 9 GIPR structures, where it is R346 and R338 respectively; it is an arginine in all three receptors. That position was independently mutated in GLP-1R and reported to modulate receptor activation a decade before this model existed. Before the model was trained we specified and committed a single pass criterion, that attention mass would concentrate in the cytoplasmic third. It was met: enrichment 2.07-fold at 6X18 and 1.94-fold at 6XOX, p < 0.0001 in both. This is a result about activation state rather than about pathway preference; no structure in training carried a pathway label. It recovers known activation biology at the level of a single residue: the position carrying the maximum is the TM6 member of the cytoplasmic polar network, a feature independently described as holding the receptor base closed and as breaking when the receptor couples to a G protein. That a model trained without positional supervision places its attention maximum on a characterized activation residue, in a receptor class it never saw, is what makes these maps a usable input into structure-aware biased-ligand discovery.",
  "abstract_shown": true,
  "affiliations": [
    "Deep EigenMatics, Inc."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Stephen G. Odaibo"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1s566nxf3932q.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010433/v1",
  "fulltext_url": null,
  "id": "1s566nxf3932q",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010433/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": "W7221757437",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-13",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/1s566nxf3932q.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:24Z",
      "native_id": "10.26434/chemrxiv.15010433",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010433/v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Receptor Mechanisms and Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "A class A-trained GPCR activation-state classifier transfers to class B1, with attention mass in GLP-1R, GCGR and GIPR spiking at arginine 6.37x37, the TM6 member of the cytoplasmic polar network",
  "title_text": "A class A-trained GPCR activation-state classifier transfers to class B1, with attention mass in GLP-1R, GCGR and GIPR spiking at arginine 6.37x37, the TM6 member of the cytoplasmic polar network",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:24Z",
  "url": "https://research.draconitic.com/paper/1s566nxf3932q",
  "venue": "ChemRxiv",
  "versions": []
}