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).  As important modulators of human purinergic signaling, P2X1 receptors transport calcium, regulating multiple physiological processes, and are promising therapeutic targets for male contraception and inflammation. However, the development of drugs that target the P2X1 receptor, such as the antagonist NF449, is greatly hindered by the unclear molecular mechanism of ligand binding modes and receptor activation. Qiang et al. 2025 reported the structures of the P2X1 receptor in complex with the endogenous agonist ATP or the competitive antagonist NF449. The P2X1 receptor displays distinct conformational features when bound to different types of compounds. Despite coupling to the agonist ATP, the receptor adopts a desensitized conformation that arrests the ions in the transmembrane (TM) domain, aligning with the nature of the high desensitization rates of the P2X1 receptor. The antagonist NF449 not only occupies the orthosteric pocket of ATP but also interacts with the dorsal fin, left flipper, and head domains, suggesting a unique binding mode to perform both orthosteric and allosteric mechanisms of NF449 inhibition. A novel lipid binding site adjacent to the TM helices and lower body of P2X1, which is critical for receptor activation, was identified. Further functional assay results and structural alignments revealed the high conservation of this lipid binding site in P2X receptors, indicating important modulatory roles upon lipid binding (Qiang et al. 2025).