1. Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors
- Author
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Philippe Sarret, Kirill Kovalev, Alexey Mishin, Toru Maruyama, Aleksandra Luginina, Gye Won Han, Margarita Ergasheva, Egor Marin, Vadim Cherezov, Anastasiia Gusach, Anastasiia Stepko, Nilkanth Patel, Valentin Borshchevskiy, Benjamin Stauch, Élie Besserer-Offroy, Petr Popov, Andrii Ishchenko, Mikhail B. Shevtsov, Taku Fujimoto, Jean-Michel Longpré, Rebecca L. Brouillette, Daria Romanovskaia, Vsevolod Katritch, and Valentin Gordeliy
- Subjects
Models, Molecular ,0301 basic medicine ,Protein Conformation ,Science ,Central nervous system ,General Physics and Astronomy ,Crystallography, X-Ray ,Ligands ,Protein Engineering ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Leukotriene D4 ,03 medical and health sciences ,0302 clinical medicine ,Protein structure ,G protein-coupled receptors ,Sf9 Cells ,medicine ,Animals ,Humans ,Computer Simulation ,lcsh:Science ,Receptor ,X-ray crystallography ,Receptors, Leukotriene ,Mutation ,Multidisciplinary ,Chemistry ,Mutagenesis ,HEK 293 cells ,General Chemistry ,Protein engineering ,Asthma ,3. Good health ,Molecular Docking Simulation ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Membrane protein ,Cancer research ,lcsh:Q ,ddc:500 ,030217 neurology & neurosurgery - Abstract
Cysteinyl leukotriene G protein-coupled receptors CysLT1 and CysLT2 regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT1R has been used for treating asthma and associated diseases for over two decades, CysLT2R 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 CysLT2R in complex with three dual CysLT1R/CysLT2R 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., Cysteinyl leukotriene G protein-coupled receptors CysLT1 and CysLT2 regulate pro-inflammatory responses associated with allergic disorders. Here, authors describe four crystal structures of CysLT2R in complex with three dual CysLT1R/CysLT2R antagonists, which shed light on CysLTR ligand selectivity.
- Published
- 2019
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