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Nat Commun. 2019 Dec 6;10(1):5573. doi: 10.1038/s41467-019-13348-2.

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

Author information

1
Research Сenter for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia, 141701.
2
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada.
3
Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA.
4
Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA.
5
Merck Research Laboratories, Merck & Co Inc., 770 Sumneytown Pike, West Point, PA, 19486, USA.
6
Center for Computational and Data Intensive Science and Engineering, Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Building 1, Moscow, Russia, 121205.
7
Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA.
8
Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka, 618-8585, Japan.
9
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090, Vienna, Austria.
10
Institute of Complex Systems (ICS), ICS-6: Structural Biochemistry, Research Center Jülich, Jülich, Germany.
11
Institut de Biologie Structurale Jean-Pierre Ebel, Université Grenoble Alpes-Commissariat à l'Energie Atomique et aux Energies Alternatives-CNRS, Grenoble, France.
12
JuStruct: Jülich Center for Structural Biology, Research Center Jülich, Jülich, Germany.
13
Institute of Crystallography, RWTH Aachen University, Aachen, Germany.
14
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada. Philippe.Sarret@USherbrooke.ca.
15
Research Сenter for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia, 141701. mishinalexej@gmail.com.
16
Research Сenter for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny, Russia, 141701. cherezov@usc.edu.
17
Bridge Institute, Michelson Center for Convergent Bioscience, University of Southern California, Los Angeles, CA, 90089, USA. cherezov@usc.edu.
18
Department of Chemistry, University of Southern California, Los Angeles, CA, 90089, USA. cherezov@usc.edu.
19
Department of Biological Sciences, University of Southern California, Los Angeles, CA, 90089, USA. cherezov@usc.edu.

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.

PMID:
31811124
DOI:
10.1038/s41467-019-13348-2
Free PMC Article

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