Purinergic P2X receptors: Structural models and analysis of ligand-target interaction
Purinergic P2X receptors: Structural models and analysis of ligand-target interaction
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DOI：
10.1016/j.ejmech.2014.10.071
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发表时间：
2015-01-07
影响因子：
6.7
通讯作者：
Volpini, Rosaria
中科院分区：
文献类型：
--
作者：
Dal Ben, Diego;Buccioni, Michela;Volpini, Rosaria
嘌呤能的P2X受体是由内源性配体ATP激活的配体门控阳离子通道。它们从7个克隆的亚型(P2X1-7)以同源或异源三聚体的形式组装，所有三聚体亚基都呈现一个共同的拓扑结构，包括细胞内的N-末端和C-末端、两个跨膜区和一个大的胞外区。这些膜蛋白几乎存在于所有哺乳动物组织中，并调节生理和病理条件下的各种反应。因此，选择性激活或阻断特定的P2X受体亚型的配体的开发是获得治疗疼痛、癌症、炎症以及神经、心血管和内分泌疾病的新的药理工具的一种有前途的策略。斑马鱼P2X4受体非活性形式和结合活性形式的晶体结构的发表为分析受体结构、解释突变数据以及描述配体结合和受体激活机制提供了结构数据。此外，提供对P2X受体亚型具有选择性的ATP竞争性配体的可用性支持设计具有可能改善药代动力学特征的新的有效和选择性配体，最终目的是获得新药。这项研究描述了为建立人和大鼠处于非活动状态和活动状态的P2X受体的结构模型而进行的分子模拟研究。这些模型可以分析一些非保守残基在ATP结合位点上的作用，并研究受体与一些非特异性或亚型选择性激动剂和拮抗剂的相互作用。(C)2014年爱思唯尔·马森公司。版权所有。
The purinergic P2X receptors are ligand-gated cation channels activated by the endogenous ligand ATP. They assemble as homo- or heterotrimers from seven cloned subtypes (P2X1-7) and all trimer subunits present a common topology consisting in intracellular N- and C- termini, two transmembrane domains and a large extracellular domain. These membrane proteins are present in virtually all mammalian tissues and regulate a large variety of responses in physio- and pathological conditions. The development of ligands that selectively activate or block specific P2X receptor subtypes hence represents a promising strategy to obtain novel pharmacological tools for the treatment of pain, cancer, inflammation, and neurological, cardiovascular, and endocrine diseases. The publication of the crystal structures of zebrafish P2X4 receptor in inactive and ATP-bound active forms provided structural data for the analysis of the receptor structure, the interpretation of mutagenesis data, and the depiction of ligand binding and receptor activation mechanism. In addition, the availability of ATP-competitive ligands presenting selectivity for P2X receptor subtypes supports the design of new potent and selective ligands with possibly improved pharmacokinetic profiles, with the final aim to obtain new drugs. This study describes molecular modelling studies performed to develop structural models of the human and rat P2X receptors in inactive and active states. These models allowed to analyse the role of some non-conserved residues at ATP binding site and to study the receptor interaction with some non-specific or subtype selective agonists and antagonists. (C) 2014 Elsevier Masson SAS. All rights reserved.