Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

Anastasiia Gusach, Aleksandra Luginina, Egor Marin, Rebecca L. Brouillette, Élie Besserer-Offroy, Jean-Michel Longpré, Andrii Ishchenko, Petr Popov, Nilkanth Patel, Taku Fujimoto, Toru Maruyama, Benjamin Stauch, Margarita Ergasheva, Daria Romanovskaia, Anastasiia Stepko, Kirill Kovalev, Mikhail Shevtsov, Valentin Gordeliy, Gye Won Han, Vsevolod Katritch, Valentin Borshchevskiy, Philippe Sarret (), Alexey Mishin () and Vadim Cherezov ()
Additional contact information
Anastasiia Gusach: Moscow Institute of Physics and Technology
Aleksandra Luginina: Moscow Institute of Physics and Technology
Egor Marin: Moscow Institute of Physics and Technology
Rebecca L. Brouillette: Université de Sherbrooke
Élie Besserer-Offroy: Université de Sherbrooke
Jean-Michel Longpré: Université de Sherbrooke
Andrii Ishchenko: University of Southern California
Petr Popov: Moscow Institute of Physics and Technology
Nilkanth Patel: University of Southern California
Taku Fujimoto: Ono Pharmaceutical Co., Ltd.
Toru Maruyama: Ono Pharmaceutical Co., Ltd.
Benjamin Stauch: University of Southern California
Margarita Ergasheva: Moscow Institute of Physics and Technology
Daria Romanovskaia: Moscow Institute of Physics and Technology
Anastasiia Stepko: Moscow Institute of Physics and Technology
Kirill Kovalev: Moscow Institute of Physics and Technology
Mikhail Shevtsov: Moscow Institute of Physics and Technology
Valentin Gordeliy: Moscow Institute of Physics and Technology
Gye Won Han: University of Southern California
Vsevolod Katritch: University of Southern California
Valentin Borshchevskiy: Moscow Institute of Physics and Technology
Philippe Sarret: Université de Sherbrooke
Alexey Mishin: Moscow Institute of Physics and Technology
Vadim Cherezov: Moscow Institute of Physics and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13348-2

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