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Druggable negative allosteric site of P2X3 receptors

文献类型：期刊论文

作者Wang, Jin1,4; Wang, Yao1,4; Cui, Wen-Wen1; Huang, Yichen4; Yang, Yang1; Liu, Yan1; Zhao, Wen-Shan1,2; Cheng, Xiao-Yang1; Sun, Wang-Sheng2; Cao, Peng3
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2018-05-08
卷号115期号:19页码:4939-4944
关键词P2X3 receptors allosteric inhibition X-ray crystallography AF-219 AF-353
ISSN号0027-8424
DOI10.1073/pnas.1800907115
文献子类Article
英文摘要Allosteric modulation provides exciting opportunities for drug discovery of enzymes, ion channels, and G protein-coupled receptors. As cation channels gated by extracellular ATP, P2X receptors have attracted wide attention as new drug targets. Although small molecules targeting P2X receptors have entered into clinical trials for rheumatoid arthritis, cough, and pain, negative allosteric modulation of these receptors remains largely unexplored. Here, combining X-ray crystallography, computational modeling, and functional studies of channel mutants, we identified a negative allosteric site on P2X3 receptors, fostered by the left flipper (LF), lower body (LB), and dorsal fin (DF) domains. Using two structurally analogous subtype-specific allosteric inhibitors of P2X3, AF-353 and AF-219, the latter being a drug candidate under phase II clinical trials for refractory chronic cough and idiopathic pulmonary fibrosis, we defined the molecular interactions between the drugs and receptors and the mechanism by which allosteric changes in the LF, DF, and LB domains modulate ATP activation of P2X3. Our detailed characterization of this druggable allosteric site should inspire new strategies to develop P2X3-specific allosteric modulators for clinical use.
WOS关键词ION-CHANNEL ; ATP-BINDING ; ACTIVATION ; DOMAIN ; ANTAGONIST ; MODULATION ; MECHANISM ; INSIGHTS ; CNS
资助项目National Key R&D Program of China[2016YFA0502800] ; National Key R&D Program of China[2014CB910300/02] ; National Natural Science Foundation of China[31570832] ; National Natural Science Foundation of China[31570838] ; National Natural Science Foundation of China[31170787] ; National Natural Science Foundation of China[31400707] ; National Natural Science Foundation of China[31222018] ; National Natural Science Foundation of China[31650110469] ; National Postdoctoral Program for Innovative Talents[BX201700306] ; Opening Project of State Key Laboratory of Drug Research in Shanghai Institute of Materia Medica[SIMM1601KF-02]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000431639100056
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/279765]  
专题新药研究国家重点实验室
中科院受体结构与功能重点实验室
通讯作者Wang, Rui; Hattori, Motoyuki; Yu, Ye
作者单位1.Shanghai Jiao Tong Univ, Sch Med, Inst Med Sci, Dept Pharmacol & Chem Biol, Shanghai 200025, Peoples R China;
2.Lanzhou Univ, Sch Basic Med Sci, Key Lab Preclin Study New Drugs Gansu Prov, Lanzhou 730000, Gansu, Peoples R China;
3.Nanjing Univ Chinese Med, Hosp Integrated Tradit Chinese & Western Med, Nanjing 210023, Jiangsu, Peoples R China;
4.Fudan Univ, Collaborat Innovat Ctr Genet & Dev, Sch Life Sci, Dept Physiol & Biophys,State Key Lab Genet Engn, Shanghai 200438, Peoples R China;
5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 200025, Peoples R China;
6.Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA
推荐引用方式
GB/T 7714		 Wang, Jin,Wang, Yao,Cui, Wen-Wen,et al. Druggable negative allosteric site of P2X3 receptors[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2018,115(19):4939-4944.
APA Wang, Jin.,Wang, Yao.,Cui, Wen-Wen.,Huang, Yichen.,Yang, Yang.,...&Yu, Ye.(2018).Druggable negative allosteric site of P2X3 receptors.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,115(19),4939-4944.
MLA Wang, Jin,et al."Druggable negative allosteric site of P2X3 receptors".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 115.19(2018):4939-4944.

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来源：上海药物研究所

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