Molecular Pharmacology of P2X Receptors: Exploring Druggable Domains Revealed by Structural Biology.
Molecular Pharmacology of P2X Receptors: Exploring Druggable Domains Revealed by Structural Biology.
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DOI：
10.3389/fphar.2022.925880
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发表时间：
2022
影响因子：
5.6
通讯作者：
Mansoor, Steven E.
中科院分区：
文献类型：
--
作者：
Oken, Adam C.;Krishnamurthy, Ipsita;Savage, Jonathan C.;Lisi, Nicolas E.;Godsey, Michael H.;Mansoor, Steven E.
关键词：
胞外三磷酸腺苷是一种重要的信号分子，存在于细胞环境中的多种浓度中。感知细胞外ATP的非选择性阳离子通道家族被称为P2X受体(P2XRs)，由七个亚型(P2X1-P2X7)组成，它们组装成功能性的同三聚体和异三聚体离子通道。每个P2XR都被不同浓度的细胞外ATP激活，从高纳米分子到低毫米分子不等。P2XRs参与心血管、免疫和中枢神经系统的多种生理和病理生理过程，对应于每个亚型的时空表达、调节和激活。P2XRs的治疗潜力是一个新兴的研究领域，在这一领域中，结构生物学似乎已经超过了药物化学，因为有几种已发表的P2XR结构，但目前还没有FDA批准的针对这些离子通道的药物。低温电子显微镜通过揭示和表征新的配体结合位点，非常适合于基于结构的药物设计。本文综述了P2XRs的结构元素，包括胞外正构ATP结合部位、胞外变构调节剂部位、通道孔和细胞质亚结构，重点介绍了潜在的治疗配体的开发。
Extracellular ATP is a critical signaling molecule that is found in a wide range of concentrations across cellular environments. The family of nonselective cation channels that sense extracellular ATP, termed P2X receptors (P2XRs), is composed of seven subtypes (P2X1-P2X7) that assemble as functional homotrimeric and heterotrimeric ion channels. Each P2XR is activated by a distinct concentration of extracellular ATP, spanning from high nanomolar to low millimolar. P2XRs are implicated in a variety of physiological and pathophysiological processes in the cardiovascular, immune, and central nervous systems, corresponding to the spatiotemporal expression, regulation, and activation of each subtype. The therapeutic potential of P2XRs is an emerging area of research in which structural biology has seemingly exceeded medicinal chemistry, as there are several published P2XR structures but currently no FDA-approved drugs targeting these ion channels. Cryogenic electron microscopy is ideally suited to facilitate structure-based drug design for P2XRs by revealing and characterizing novel ligand-binding sites. This review covers structural elements in P2XRs including the extracellular orthosteric ATP-binding site, extracellular allosteric modulator sites, channel pore, and cytoplasmic substructures, with an emphasis on potential therapeutic ligand development.
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