Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs
Category
Published on
Type
journal-article
Author
Aleksandra Luginina and Anastasiia Gusach and Egor Marin and Alexey Mishin and Rebecca Brouillette and Petr Popov and Anna Shiriaeva and Élie Besserer-Offroy and Jean-Michel Longpré and Elizaveta Lyapina and Andrii Ishchenko and Nilkanth Patel and Vitaly Polovinkin and Nadezhda Safronova and Andrey Bogorodskiy and Evelina Edelweiss and Hao Hu and Uwe Weierstall and Wei Liu and Alexander Batyuk and Valentin Gordeliy and Gye Won Han and Philippe Sarret and Vsevolod Katritch and Valentin Borshchevskiy and Vadim Cherezov
Citation
Luginina, A. et al., 2019. Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. Science Advances, 5(10), p.eaax2518. Available at: http://dx.doi.org/10.1126/sciadv.aax2518.
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.
DOI
Funding
NSF-STC Biology with X-ray Lasers (NSF-1231306)
