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

Aleksandra Luginina, Anastasiia Gusach, Egor Marin, Alexey Mishin, Rebecca Brouillette, Petr Popov, Anna Shiriaeva, Élie Besserer-Offroy, Jean Michel Longpré, Elizaveta Lyapina, Andrii Ishchenko, Nilkanth Patel, Vitaly Polovinkin, Nadezhda Safronova, Andrey Bogorodskiy, Evelina Edelweiss, Hao Hu, Uwe Weierstall, Wei Liu, Alexander BatyukValentin Gordeliy, Gye Won Han, Philippe Sarret, Vsevolod Katritch, Valentin Borshchevskiy, Vadim Cherezov

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


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 languageEnglish (US)
Article numberaax2518
JournalScience Advances
Issue number10
StatePublished - Oct 9 2019

ASJC Scopus subject areas

  • General


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