The first 3D structure of an inhibitory anion-selective Cys-loop receptor, the Caenorhabditis elegans glutamate-gated chloride channel α (GluCl), has been determined at 3.3 Å resolution. The structure reveals the arrangement of the receptor subunits and the binding sites for neurotransmitters and modulators. Ivermectin, a broad-spectrum antiparasitic agent, binds in the transmembrane domain and stabilizes an open pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, while picrotoxin directly occludes the pore near its cytosolic base. The structure provides insights into the mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors. The GluCl structure shows that the pore is in an open conformation, allowing chloride ion passage. The structure also reveals the selectivity for anions, with the pore conformation and electrostatic potential playing key roles. The study highlights the importance of the M2 helix in stabilizing the open state and the role of specific residues in ion selectivity. The findings advance understanding of the molecular mechanisms of fast neuronal inhibition and the importance of Cys-loop receptors in nervous system function.The first 3D structure of an inhibitory anion-selective Cys-loop receptor, the Caenorhabditis elegans glutamate-gated chloride channel α (GluCl), has been determined at 3.3 Å resolution. The structure reveals the arrangement of the receptor subunits and the binding sites for neurotransmitters and modulators. Ivermectin, a broad-spectrum antiparasitic agent, binds in the transmembrane domain and stabilizes an open pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, while picrotoxin directly occludes the pore near its cytosolic base. The structure provides insights into the mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors. The GluCl structure shows that the pore is in an open conformation, allowing chloride ion passage. The structure also reveals the selectivity for anions, with the pore conformation and electrostatic potential playing key roles. The study highlights the importance of the M2 helix in stabilizing the open state and the role of specific residues in ion selectivity. The findings advance understanding of the molecular mechanisms of fast neuronal inhibition and the importance of Cys-loop receptors in nervous system function.