1.A.7.1.1
ATP-gated cation channel (purinoceptor or ATP-neuroreceptor). Residues Glu52-Gly96 play roles in agonist binding and channel gating (Allsopp et al., 2011).  The rat protein is 89% identical to the human ortholog. Mutations likely to confer ivermectin sensitivity to human P2X1 have been proposed (Pasqualetto et al. 2018).  The P2X1 receptor is a trimeric ligand-gated ion channel that plays an important role in urogenital and immune functions. Bennetts et al. 2024 employed cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in an ATP-bound desensitised state and an NF449-bound closed state. NF449, a potent P2X1 receptor antagonist, engages the receptor distinctively, while ATP, the endogenous ligand, binds in a manner consistent with other P2X receptors. To explore the molecular basis of receptor inhibition, activation, and ligand interactions, key residues involved in ligand and metal ion binding were mutated. Radioligand binding assays with [³H]-α,β-methylene ATP and intracellular calcium ion influx assays were used to evaluate the effects of these mutations. These experiments validated key ligand-receptor interactions and identified conserved and non-conserved residues critical for ligand binding or receptor modulation (Bennetts et al. 2024).