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 Batyuk; Valentin Gordeliy; Gye Won Han; Philippe Sarret; Vsevolod Katritch; Valentin Borshchevskiy; Vadim Cherezov

doi:10.1126/sciadv.aax2518

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 journal › Article › peer-review

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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	https://doi.org/10.1126/sciadv.aax2518
State	Published - Oct 9 2019

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10.1126/sciadv.aax2518

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Luginina, A., Gusach, A., Marin, E., Mishin, A., Brouillette, R., Popov, P., Shiriaeva, A., Besserer-Offroy, É., Longpré, J. M., Lyapina, E., Ishchenko, A., Patel, N., Polovinkin, V., Safronova, N., Bogorodskiy, A., Edelweiss, E., Hu, H., Weierstall, U., Liu, W., ... Cherezov, V. (2019). Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. Science Advances, 5(10), Article aax2518. https://doi.org/10.1126/sciadv.aax2518

Luginina, A, Gusach, A, Marin, E, Mishin, A, Brouillette, R, Popov, P, Shiriaeva, A, Besserer-Offroy, É, Longpré, JM, 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, GW, Sarret, P, Katritch, V, Borshchevskiy, V & Cherezov, V 2019, 'Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs', Science Advances, vol. 5, no. 10, aax2518. https://doi.org/10.1126/sciadv.aax2518

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title = "Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs",

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.",

author = "Aleksandra Luginina and Anastasiia Gusach and Egor Marin and Alexey Mishin and Rebecca Brouillette and Petr Popov and Anna Shiriaeva and {\'E}lie Besserer-Offroy and Longpr{\'e}, {Jean Michel} 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 Han, {Gye Won} and Philippe Sarret and Vsevolod Katritch and Valentin Borshchevskiy and Vadim Cherezov",

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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

N1 - Publisher Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

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.

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

Abstract

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Crystal structure of cysteinyl leukotriene receptor 1 in complex with pranlukast

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

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

Abstract

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Datasets

Crystal structure of cysteinyl leukotriene receptor 1 in complex with pranlukast

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

Cite this