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

Author:

Gusach AnastasiiaORCID,Luginina Aleksandra,Marin Egor,Brouillette Rebecca L.,Besserer-Offroy ÉlieORCID,Longpré Jean-Michel,Ishchenko AndriiORCID,Popov Petr,Patel Nilkanth,Fujimoto Taku,Maruyama Toru,Stauch BenjaminORCID,Ergasheva Margarita,Romanovskaia DariaORCID,Stepko AnastasiiaORCID,Kovalev Kirill,Shevtsov Mikhail,Gordeliy Valentin,Han Gye Won,Katritch VsevolodORCID,Borshchevskiy ValentinORCID,Sarret Philippe,Mishin AlexeyORCID,Cherezov VadimORCID

Abstract

AbstractCysteinyl 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.

Funder

Russian Science Foundation

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

GPCR Consortium

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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