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Title: Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs

Abstract

The G protein–coupled cysteinyl leukotriene receptor CysLT1R mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLT1R antagonists are widely prescribed as antiasthmatic drugs; however, these drugs demonstrate low effectiveness in some patients and exhibit a variety of side effects. To gain deeper understanding into the functional mechanisms of CysLTRs, we determined the crystal structures of CysLT1R bound to two chemically distinct antagonists, zafirlukast and pranlukast. The structures reveal unique ligand-binding modes and signaling mechanisms, including lateral ligand access to the orthosteric pocket between transmembrane helices TM4 and TM5, an atypical pattern of microswitches, and a distinct four-residue–coordinated sodium site. These results provide important insights and structural templates for rational discovery of safer and more effective drugs.

Authors:
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [2];  [3];  [4]; ORCiD logo [2]; ORCiD logo [2]; ORCiD logo [1];  [5]; ORCiD logo [4]; ORCiD logo [6]; ORCiD logo [1];  [1];  [7]; ORCiD logo [8]; ORCiD logo [8];  [8]; ORCiD logo [9] more »;  [10]; ORCiD logo [11]; ORCiD logo [2]; ORCiD logo [4]; ORCiD logo [12]; ORCiD logo [13] « less
  1. Moscow Inst. of Physics and Technology, Dolgoprudny (Russia)
  2. Univ. de Sherbrooke, Quebec (Canada)
  3. Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Skolkovo Inst. of Science and Technology, Moscow (Russia)
  4. Univ. of Southern California, Los Angeles, CA (United States)
  5. Univ. of Southern California, Los Angeles, CA (United States); Merck Research Labs, West Point, PA (United States)
  6. Inst. of Complex Systems, Juelich (Germany); Univ. Grenoble Alpes-CEA-CNRS, Grenoble (France); Czech Academy of Sciences, Prague (Czech Republic)
  7. Univ. Grenoble Alpes-CEA-CNRS, Grenoble (France)
  8. Arizona State Univ., Tempe, AZ (United States)
  9. SLAC National Accelerator Lab., Menlo Park, CA (United States)
  10. Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Inst. of Complex Systems, Juelich (Germany); Univ. Grenoble Alpes-CEA-CNRS, Grenoble (France); Juelich Center for Structural Biology, Juelich (Germany); RWTH Aachen Univ., Aachen (Germany)
  11. Univ. of Southern California, Los Angeles, CA (United States). Center for Energy Nanoscience and Technology
  12. Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Inst. of Complex Systems, Juelich (Germany); Juelich Center for Structural Biology, Juelich (Germany)
  13. Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Univ. of Southern California, Los Angeles, CA (United States)
Publication Date:
Research Org.:
SLAC National Accelerator Lab., Menlo Park, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1577320
Grant/Contract Number:  
AC02-76SF00515; 1231306; R21 DA042298; R35 GM127086; R01 GM124152; FDN-148413; 18-02-40020; 16-14-10273
Resource Type:
Accepted Manuscript
Journal Name:
Science Advances
Additional Journal Information:
Journal Volume: 5; Journal Issue: 10; Journal ID: ISSN 2375-2548
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Luginina, Aleksandra, Gusach, Anastasiia, Marin, Egor, Mishin, Alexey, Brouillette, Rebecca, Popov, Petr, Shiriaeva, Anna, Besserer-Offroy, Élie, Longpré, Jean -Michel, Lyapina, Elizaveta, Ishchenko, Andrii, Patel, Nilkanth, Polovinkin, Vitaly, Safronova, Nadezhda, Bogorodskiy, Andrey, Edelweiss, Evelina, Hu, Hao, Weierstall, Uwe, Liu, Wei, Batyuk, Alexander, Gordeliy, Valentin, Han, Gye Won, Sarret, Philippe, Katritch, Vsevolod, Borshchevskiy, Valentin, and Cherezov, Vadim. Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. United States: N. p., 2019. Web. doi:10.1126/sciadv.aax2518.
Luginina, Aleksandra, Gusach, Anastasiia, Marin, Egor, Mishin, Alexey, Brouillette, Rebecca, Popov, Petr, Shiriaeva, Anna, Besserer-Offroy, Élie, Longpré, Jean -Michel, Lyapina, Elizaveta, Ishchenko, Andrii, Patel, Nilkanth, Polovinkin, Vitaly, Safronova, Nadezhda, Bogorodskiy, Andrey, Edelweiss, Evelina, Hu, Hao, Weierstall, Uwe, Liu, Wei, Batyuk, Alexander, Gordeliy, Valentin, Han, Gye Won, Sarret, Philippe, Katritch, Vsevolod, Borshchevskiy, Valentin, & Cherezov, Vadim. Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. United States. doi:10.1126/sciadv.aax2518.
Luginina, Aleksandra, Gusach, Anastasiia, Marin, Egor, Mishin, Alexey, Brouillette, Rebecca, Popov, Petr, Shiriaeva, Anna, Besserer-Offroy, Élie, Longpré, Jean -Michel, Lyapina, Elizaveta, Ishchenko, Andrii, Patel, Nilkanth, Polovinkin, Vitaly, Safronova, Nadezhda, Bogorodskiy, Andrey, Edelweiss, Evelina, Hu, Hao, Weierstall, Uwe, Liu, Wei, Batyuk, Alexander, Gordeliy, Valentin, Han, Gye Won, Sarret, Philippe, Katritch, Vsevolod, Borshchevskiy, Valentin, and Cherezov, Vadim. Wed . "Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs". United States. doi:10.1126/sciadv.aax2518. https://www.osti.gov/servlets/purl/1577320.
@article{osti_1577320,
title = {Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs},
author = {Luginina, Aleksandra and Gusach, Anastasiia and Marin, Egor and Mishin, Alexey and Brouillette, Rebecca and Popov, Petr and Shiriaeva, Anna and Besserer-Offroy, Élie and Longpré, Jean -Michel and Lyapina, Elizaveta and Ishchenko, Andrii and Patel, Nilkanth and Polovinkin, Vitaly and Safronova, Nadezhda and Bogorodskiy, Andrey and Edelweiss, Evelina and Hu, Hao and Weierstall, Uwe and Liu, Wei and Batyuk, Alexander and Gordeliy, Valentin and Han, Gye Won and Sarret, Philippe and Katritch, Vsevolod and Borshchevskiy, Valentin and Cherezov, Vadim},
abstractNote = {The G protein–coupled cysteinyl leukotriene receptor CysLT1R mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLT1R antagonists are widely prescribed as antiasthmatic drugs; however, these drugs demonstrate low effectiveness in some patients and exhibit a variety of side effects. To gain deeper understanding into the functional mechanisms of CysLTRs, we determined the crystal structures of CysLT1R bound to two chemically distinct antagonists, zafirlukast and pranlukast. The structures reveal unique ligand-binding modes and signaling mechanisms, including lateral ligand access to the orthosteric pocket between transmembrane helices TM4 and TM5, an atypical pattern of microswitches, and a distinct four-residue–coordinated sodium site. These results provide important insights and structural templates for rational discovery of safer and more effective drugs.},
doi = {10.1126/sciadv.aax2518},
journal = {Science Advances},
number = 10,
volume = 5,
place = {United States},
year = {2019},
month = {10}
}

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    Works referencing / citing this record:

    Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
    text, January 2019


    Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors
    journal, December 2019


    Structural insights into melatonin receptors
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