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Proc Natl Acad Sci U S A. 2018 May 8;115(19):4939-4944. doi: 10.1073/pnas.1800907115. Epub 2018 Apr 19.

Druggable negative allosteric site of P2X3 receptors.

Author information

1
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 200438 Shanghai, China.
2
Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China.
3
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, 730000 Lanzhou, China.
4
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, 210023 Nanjing, China.
5
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 200025 Shanghai, China.
6
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030.
7
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences, Lanzhou University, 730000 Lanzhou, China; wangrui@lzu.edu.cn hattorim@fudan.edu.cn yuye@shsmu.edu.cn.
8
State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, Department of Physiology and Biophysics, School of Life Sciences, Fudan University, 200438 Shanghai, China; wangrui@lzu.edu.cn hattorim@fudan.edu.cn yuye@shsmu.edu.cn.
9
Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 200025 Shanghai, China; wangrui@lzu.edu.cn hattorim@fudan.edu.cn yuye@shsmu.edu.cn.

Abstract

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.

KEYWORDS:

AF-219; AF-353; P2X3 receptors; X-ray crystallography; allosteric inhibition

PMID:
29674445
PMCID:
PMC5948998
DOI:
10.1073/pnas.1800907115
[Indexed for MEDLINE]
Free PMC Article

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