6RZ5

XFEL crystal structure of the human cysteinyl leukotriene receptor 1 in complex with zafirlukast

Summary for 6RZ5

• Entry DOI: 10.2210/pdb6rz5/pdb
• Descriptor: Cysteinyl leukotriene receptor 1,Soluble cytochrome b562,Cysteinyl leukotriene receptor 1, zafirlukast, (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate, ... (7 entities in total)
• Functional Keywords: gpcr, lcp, membrane protein, cysteinyl leukotriene, ltd4, cyslt1, cysltr1, cyslt1r, asthma, zafirlukast, bril, sodium site, cysteinyl leukotriene receptor 1, xfel, serial femtosecond crystallography, sfx
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 109293.40

Authors

Luginina, A.,Gusach, A.,Marin, E.,Mishin, A.,Brouillette, R.,Popov, P.,Shiryaeva, A.,Besserer-Offroy, E.,Longpre, J.M.,Lyapina, E.,Ishchenko, A.,Patel, N.,Polovinkin, V.,Safronova, N.,Bogorodskiy, A.,Edelweiss, E.,Liu, W.,Batyuk, A.,Gordeliy, V.,Han, G.W.,Sarret, P.,Katritch, V.,Borshchevskiy, V.,Cherezov, V. (deposition date: 2019-06-12, release date: 2019-10-30, Last modification date: 2024-11-13)

Primary citation

Luginina, A.,Gusach, A.,Marin, E.,Mishin, A.,Brouillette, R.,Popov, P.,Shiriaeva, A.,Besserer-Offroy, E.,Longpre, J.M.,Lyapina, E.,Ishchenko, A.,Patel, N.,Polovinkin, V.,Safronova, N.,Bogorodskiy, A.,Edelweiss, E.,Hu, H.,Weierstall, U.,Liu, W.,Batyuk, A.,Gordeliy, V.,Han, G.W.,Sarret, P.,Katritch, V.,Borshchevskiy, V.,Cherezov, V.
Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs.
Sci Adv, 5:eaax2518-eaax2518, 2019

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

PubMed: 31633023
DOI: 10.1126/sciadv.aax2518

Experimental method

X-RAY DIFFRACTION (2.53 Å)