期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13348-2
关键词
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资金
- Russian Science Foundation [19-14-00261, 18-74-00117]
- GPCR consortium
- Ministry of Science and Higher Education of the Russian Federation [6.9909.2017/6.7]
- Grenoble Instruct Centre (ISBG) [UMS 3518 CNRS-CEA-UJF-EMBL]
- French Infrastructure for Integrated Structural Biology (FRISBI) [ANR-10-INSB-05-02]
- New Generation of Drugs for Alzheimer's Disease project (GRAL) within the Grenoble Partnership for Structural Biology [ANR-10-LABX-49-01]
- EMBO [ALTF 677-2014]
- Institut de Pharmacologie de Sherbrooke
- Centre d'excellence en neurosciences de l'Universite de Sherbrooke
- Canadian Institutes of Health Research
- Fonds de Recherche en Sante du Quebec
- Russian Science Foundation [19-14-00261, 18-74-00117] Funding Source: Russian Science Foundation
Cysteinyl leukotriene G protein-coupled receptors CysLT(1) and CysLT(2) regulate proinflammatory responses associated with allergic disorders. While selective inhibition of CysLT(1)R has been used for treating asthma and associated diseases for over two decades, CysLT(2)R has recently started to emerge as a potential drug target against atopic asthma, brain injury and central nervous system disorders, as well as several types of cancer. Here, we describe four crystal structures of CysLT(2)R in complex with three dual CysLT(1)R/CysLT(2)R antagonists. The reported structures together with the results of comprehensive mutagenesis and computer modeling studies shed light on molecular determinants of CysLTR ligand selectivity and specific effects of disease-related single nucleotide variants.
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