Structural basis of ligand recognition and gating in a heteromeric Deg-3/Des-2 nicotinic acetylcholine receptor.

During evolution, nicotinic acetylcholine receptors (nAChRs) have diversified in subunit composition and ligand selectivity, enabling a conserved ion channel scaffold to support a broad range of signaling functions beyond classical synaptic transmission. Deg-3/Des-2 is a nematode-specific, calcium-permeable heteromeric α-type nicotinic receptor in sensory neurons to mediate chemosensation, nociception, and mechanotransduction, and represents a promising anthelmintic target. Here, we report cryo-electron 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-specific 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.