Cell Physiology & Pharmacology, University of Leicester, Leicester, UK.
Br J Pharmacol. 2010 Nov;161(5):961-71. doi: 10.1111/j.1476-5381.2010.00728.x.
P2X receptors for ATP are ligand gated cation channels that form from the trimeric assembly of subunits with two transmembrane segments, a large extracellular ligand binding loop, and intracellular amino and carboxy termini. The receptors are expressed throughout the body, involved in functions ranging from blood clotting to inflammation, and may provide important targets for novel therapeutics. Mutagenesis based studies have been used to develop an understanding of the molecular basis of their pharmacology with the aim of developing models of the ligand binding site. A crystal structure for the zebra fish P2X4 receptor in the closed agonist unbound state has been published recently, which provides a major advance in our understanding of the receptors. This review gives an overview of mutagenesis studies that have led to the development of a model of the ATP binding site, as well as identifying residues contributing to allosteric regulation and antagonism. These studies are discussed with reference to the crystal to provide a structural interpretation of the molecular basis of drug action.
P2X 受体是 ATP 的配体门控阳离子通道，由三个亚基组成三聚体，具有两个跨膜片段、一个大的细胞外配体结合环和细胞内的氨基和羧基末端。这些受体在全身表达，参与从凝血到炎症的各种功能，可能为新型治疗药物提供重要的靶点。基于突变的研究已被用于开发对其药理学的分子基础的理解，目的是开发配体结合位点的模型。最近发表了斑马鱼 P2X4 受体在关闭激动剂未结合状态下的晶体结构，这为我们对受体的理解提供了重大进展。这篇综述概述了导致 ATP 结合位点模型发展的突变研究，以及确定参与变构调节和拮抗作用的残基。这些研究将结合晶体进行讨论，为药物作用的分子基础提供结构解释。
