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Deg-3\/Des-2 is a nematode-specific, calcium-permeable heteromeric \u03b1-type nicotinic receptor in sensory neurons to mediate chemosensation, nociception, and mechanotransduction, and represents a promising anthelmintic target. Here, we report cryo\u2013electron microscopy structures of Deg-3\/Des-2 in its apo, agonist-bound intermediate and agonist-bound open states. Deg-3\/Des-2 adopts a 2Deg-3:3Des-2 stoichiometry. Five agonist molecules occupy intersubunit orthosteric sites, driving channel opening primarily through rotational rearrangements of the upper M2 helices that relieve a conserved hydrophobic gate and enable calcium permeation. We further identify a Deg-3\u2013specific N-terminal helix that regulates desensitization and a negatively charged extracellular vestibular helix that governs calcium permeability. Together, these structures reveal how evolutionary tuning of ligand recognition, ion selectivity, and gating within a conserved nicotinic receptor framework.<\/jats:p>","DOI":"10.1073\/pnas.2608998123","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T17:54:21Z","timestamp":1787248461000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Structural basis of ligand recognition and gating in a heteromeric Deg-3\/Des-2 nicotinic acetylcholine receptor"],"prefix":"10.1073","volume":"123","author":[{"given":"Yingjie","family":"Ning","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/030bhh786","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Science and Technology, ShanghaiTech University","place":["Shanghai, China"]},{"name":"Lingang Laboratory","place":["Shanghai, 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