Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Science advances, 2019-10, Vol.5 (10), p.eaax2518-eaax2518

Ort / Verlag

United States: AAAS

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• The G protein-coupled cysteinyl leukotriene receptor CysLT R mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLT R 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 CysLT R 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.