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.
| Original language | English (US) |
|---|---|
| Article number | aax2518 |
| Journal | Science Advances |
| Volume | 5 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 9 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Physics and Astronomy (miscellaneous)
- General
Cite this
Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. / 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.
In: Science Advances, Vol. 5, No. 10, aax2518, 09.10.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
AU - Luginina, Aleksandra
AU - Gusach, Anastasiia
AU - Marin, Egor
AU - Mishin, Alexey
AU - Brouillette, Rebecca
AU - Popov, Petr
AU - Shiriaeva, Anna
AU - Besserer-Offroy, Élie
AU - Longpré, Jean Michel
AU - Lyapina, Elizaveta
AU - Ishchenko, Andrii
AU - Patel, Nilkanth
AU - Polovinkin, Vitaly
AU - Safronova, Nadezhda
AU - Bogorodskiy, Andrey
AU - Edelweiss, Evelina
AU - Hu, Hao
AU - Weierstall, Uwe
AU - Liu, Wei
AU - Batyuk, Alexander
AU - Gordeliy, Valentin
AU - Han, Gye Won
AU - Sarret, Philippe
AU - Katritch, Vsevolod
AU - Borshchevskiy, Valentin
AU - Cherezov, Vadim
PY - 2019/10/9
Y1 - 2019/10/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85073622965&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073622965&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aax2518
DO - 10.1126/sciadv.aax2518
M3 - Article
C2 - 31633023
AN - SCOPUS:85073622965
VL - 5
JO - Indian Journal of Pure and Applied Physics
JF - Indian Journal of Pure and Applied Physics
SN - 0019-5596
IS - 10
M1 - aax2518
ER -