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Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors
Cysteinyl leukotriene G protein-coupled receptors CysLT(1) and CysLT(2) regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT(1)R has been used for treating asthma and associated diseases for over two decades, CysLT(2)R has recently started to em...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897958/ https://www.ncbi.nlm.nih.gov/pubmed/31811124 http://dx.doi.org/10.1038/s41467-019-13348-2 |
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author | Gusach, Anastasiia Luginina, Aleksandra Marin, Egor Brouillette, Rebecca L. Besserer-Offroy, Élie Longpré, Jean-Michel Ishchenko, Andrii Popov, Petr Patel, Nilkanth Fujimoto, Taku Maruyama, Toru Stauch, Benjamin Ergasheva, Margarita Romanovskaia, Daria Stepko, Anastasiia Kovalev, Kirill Shevtsov, Mikhail Gordeliy, Valentin Han, Gye Won Katritch, Vsevolod Borshchevskiy, Valentin Sarret, Philippe Mishin, Alexey Cherezov, Vadim |
author_facet | Gusach, Anastasiia Luginina, Aleksandra Marin, Egor Brouillette, Rebecca L. Besserer-Offroy, Élie Longpré, Jean-Michel Ishchenko, Andrii Popov, Petr Patel, Nilkanth Fujimoto, Taku Maruyama, Toru Stauch, Benjamin Ergasheva, Margarita Romanovskaia, Daria Stepko, Anastasiia Kovalev, Kirill Shevtsov, Mikhail Gordeliy, Valentin Han, Gye Won Katritch, Vsevolod Borshchevskiy, Valentin Sarret, Philippe Mishin, Alexey Cherezov, Vadim |
author_sort | Gusach, Anastasiia |
collection | PubMed |
description | Cysteinyl leukotriene G protein-coupled receptors CysLT(1) and CysLT(2) regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT(1)R has been used for treating asthma and associated diseases for over two decades, CysLT(2)R 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 CysLT(2)R in complex with three dual CysLT(1)R/CysLT(2)R 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. |
format | Online Article Text |
id | pubmed-6897958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68979582019-12-09 Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors Gusach, Anastasiia Luginina, Aleksandra Marin, Egor Brouillette, Rebecca L. Besserer-Offroy, Élie Longpré, Jean-Michel Ishchenko, Andrii Popov, Petr Patel, Nilkanth Fujimoto, Taku Maruyama, Toru Stauch, Benjamin Ergasheva, Margarita Romanovskaia, Daria Stepko, Anastasiia Kovalev, Kirill Shevtsov, Mikhail Gordeliy, Valentin Han, Gye Won Katritch, Vsevolod Borshchevskiy, Valentin Sarret, Philippe Mishin, Alexey Cherezov, Vadim Nat Commun Article Cysteinyl leukotriene G protein-coupled receptors CysLT(1) and CysLT(2) regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT(1)R has been used for treating asthma and associated diseases for over two decades, CysLT(2)R 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 CysLT(2)R in complex with three dual CysLT(1)R/CysLT(2)R 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. Nature Publishing Group UK 2019-12-06 /pmc/articles/PMC6897958/ /pubmed/31811124 http://dx.doi.org/10.1038/s41467-019-13348-2 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gusach, Anastasiia Luginina, Aleksandra Marin, Egor Brouillette, Rebecca L. Besserer-Offroy, Élie Longpré, Jean-Michel Ishchenko, Andrii Popov, Petr Patel, Nilkanth Fujimoto, Taku Maruyama, Toru Stauch, Benjamin Ergasheva, Margarita Romanovskaia, Daria Stepko, Anastasiia Kovalev, Kirill Shevtsov, Mikhail Gordeliy, Valentin Han, Gye Won Katritch, Vsevolod Borshchevskiy, Valentin Sarret, Philippe Mishin, Alexey Cherezov, Vadim Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors |
title | Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors |
title_full | Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors |
title_fullStr | Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors |
title_full_unstemmed | Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors |
title_short | Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors |
title_sort | structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897958/ https://www.ncbi.nlm.nih.gov/pubmed/31811124 http://dx.doi.org/10.1038/s41467-019-13348-2 |
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