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Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
A. Luginina, A. Gusach, E. Marin, A. Mishin, R. Brouillette, P. Popov, A. Shiriaeva, É. Besserer-Offroy, JM. Longpré, E. Lyapina, A. Ishchenko, N. Patel, V. Polovinkin, N. Safronova, A. Bogorodskiy, E. Edelweiss, H. Hu, U. Weierstall, W. Liu, A....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem, Research Support, U.S. Gov't, Non-P.H.S.
Grantová podpora
R01 GM124152
NIGMS NIH HHS - United States
NLK
Directory of Open Access Journals
od 2015
Freely Accessible Science Journals
od 2015
PubMed Central
od 2015
Europe PubMed Central
od 2015
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2015
PubMed
31633023
DOI
10.1126/sciadv.aax2518
Knihovny.cz E-zdroje
- MeSH
- antagonisté leukotrienů chemie metabolismus MeSH
- antiastmatika chemie metabolismus MeSH
- chromony chemie metabolismus MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- ligandy MeSH
- receptory leukotrienů chemie genetika metabolismus MeSH
- rekombinantní proteiny biosyntéza chemie izolace a purifikace MeSH
- simulace molekulového dockingu MeSH
- sodík chemie metabolismus MeSH
- terciární struktura proteinů MeSH
- tosylové sloučeniny chemie metabolismus MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
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.
Institut de Biologie Structurale J P Ebel Université Grenoble Alpes CEA CNRS Grenoble 38000 France
Linac Coherent Light Source SLAC National Accelerator Laboratory Menlo Park CA 94025 USA
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- $a 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.
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