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Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors.
Nat Commun 2019; 10(1):5573NC

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.

Authors+Show Affiliations

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

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31811124

Citation

Gusach, Anastasiia, et al. "Structural Basis of Ligand Selectivity and Disease Mutations in Cysteinyl Leukotriene Receptors." Nature Communications, vol. 10, no. 1, 2019, p. 5573.
Gusach A, Luginina A, Marin E, et al. Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors. Nat Commun. 2019;10(1):5573.
Gusach, A., Luginina, A., Marin, E., Brouillette, R. L., Besserer-Offroy, É., Longpré, J. M., ... Cherezov, V. (2019). Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors. Nature Communications, 10(1), p. 5573. doi:10.1038/s41467-019-13348-2.
Gusach A, et al. Structural Basis of Ligand Selectivity and Disease Mutations in Cysteinyl Leukotriene Receptors. Nat Commun. 2019 Dec 6;10(1):5573. PubMed PMID: 31811124.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors. AU - Gusach,Anastasiia, AU - Luginina,Aleksandra, AU - Marin,Egor, AU - Brouillette,Rebecca L, AU - Besserer-Offroy,Élie, AU - Longpré,Jean-Michel, AU - Ishchenko,Andrii, AU - Popov,Petr, AU - Patel,Nilkanth, AU - Fujimoto,Taku, AU - Maruyama,Toru, AU - Stauch,Benjamin, AU - Ergasheva,Margarita, AU - Romanovskaia,Daria, AU - Stepko,Anastasiia, AU - Kovalev,Kirill, AU - Shevtsov,Mikhail, AU - Gordeliy,Valentin, AU - Han,Gye Won, AU - Katritch,Vsevolod, AU - Borshchevskiy,Valentin, AU - Sarret,Philippe, AU - Mishin,Alexey, AU - Cherezov,Vadim, Y1 - 2019/12/06/ PY - 2019/08/27/received PY - 2019/11/01/accepted PY - 2019/12/8/entrez PY - 2019/12/8/pubmed PY - 2019/12/8/medline SP - 5573 EP - 5573 JF - Nature communications JO - Nat Commun VL - 10 IS - 1 N2 - 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. SN - 2041-1723 UR - https://www.unboundmedicine.com/medline/citation/31811124/Structural_basis_of_ligand_selectivity_and_disease_mutations_in_cysteinyl_leukotriene_receptors L2 - http://dx.doi.org/10.1038/s41467-019-13348-2 DB - PRIME DP - Unbound Medicine ER -