title: Insights into the channel gating of P2X receptors from structures, dynamics and small molecules.
abstract: P2X receptors, as ATP-gated non-selective trimeric ion channels, are permeable to Na(+), K(+) and Ca(2+). Comparing with other ligand-gated ion channel families, P2X receptors are distinct in their unique gating properties and pathophysiological roles, and have attracted attention as promising drug targets for a variety of diseases, such as neuropathic pain, multiple sclerosis, rheumatoid arthritis and thrombus. Several small molecule inhibitors for distinct P2X subtypes have entered into clinical trials. However, many questions regarding the gating mechanism of P2X remain unsolved. The structural determinations of P2X receptors at the resting and ATP-bound open states revealed that P2X receptor gating is a cooperative allosteric process involving multiple domains, which marks the beginning of the post-structure era of P2X research at atomic level. Here, we review the current knowledge on the structure-function relationship of P2X receptors, depict the whole picture of allosteric changes during the channel gating, and summarize the active sites that may contribute to new strategies for developing novel allosteric drugs targeting P2X receptors.
authors.affiliation: Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.|College of Bioscience and Biotechnology, Hu-nan Agricultural University, Changsha 410128, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D020134:Catalytic Domain; D006801:Humans; D015640:Ion Channel Gating; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D058469:Receptors, Purinergic P2X / Q000737:chemistry / Q000502:physiology*; D054852:Small Molecule Libraries / Q000494:pharmacology
chemical_list: D058469:Receptors, Purinergic P2X; D054852:Small Molecule Libraries