{
  "id": 4978188,
  "title": "Cryo-EM Structure of a Triazole alpha-Conotoxin GI Mimetic Bound to the Muscle-Type Nicotinic Acetylcholine Receptor",
  "url": "https://urgent.news/2026/09/01/cryo-em-structure-of-a-triazole-alpha-conotoxin-gi-mimetic-bound-to",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-01T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.08.31.748223v1?rss=1"
  },
  "original_language": "en",
  "account": "Researchers have developed triazole-based peptidomimetics of the -GI conotoxin, a selective antagonist of the muscle-type nicotinic acetylcholine receptor (nAChR). These triazole analogues were synthesized entirely on resin using CuAAC and RuAAC chemistry, replacing the native Cys3/13 disulfide bridge. Functional tests against human muscle nAChRs demonstrated that 1,5-triazole analogues retained low-nanomolar potency, with the lead mimetic showing activity comparable to the native -GI toxin. A breakthrough came with the use of cryo-electron microscopy, which produced the first structure of a disulfide-isostere peptidomimetic bound to a membrane receptor. This structural data reveals that the 1,5-triazole mimetic preserves the native peptide fold with exceptional fidelity, while introducing unique receptor-facing interactions not found in the original disulfide bridge. Additionally, molecular dynamics simulations confirmed that the mimetic maintains conserved hydration networks and similar conformational sampling when compared to the native peptide. These findings solidify the potential of triazole surrogates as effective alternatives to disulfide-rich peptides and provide a structural foundation for the rational design of stable conotoxin therapeutics.",
  "summary": "Disulfide-rich peptides possess exceptional potency and selectivity but are often limited by the instability and synthetic challenges associated with native disulfide bonds. Here, we report the design, synthesis, pharmacological evaluation, and structural characterisation of triazole-based peptidomimetics of the -GI conotoxin, a selective antagonist of the muscle-type nicotinic acetylcholine…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}