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.
- Authors:
-
more »
- Moscow Inst. of Physics and Technology, Dolgoprudny (Russia)
- Univ. de Sherbrooke, Quebec (Canada)
- Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Skolkovo Inst. of Science and Technology, Moscow (Russia)
- Univ. of Southern California, Los Angeles, CA (United States)
- Univ. of Southern California, Los Angeles, CA (United States); Merck Research Labs, West Point, PA (United States)
- Inst. of Complex Systems, Juelich (Germany); Univ. Grenoble Alpes-CEA-CNRS, Grenoble (France); Czech Academy of Sciences, Prague (Czech Republic)
- Univ. Grenoble Alpes-CEA-CNRS, Grenoble (France)
- Arizona State Univ., Tempe, AZ (United States)
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Inst. of Complex Systems, Juelich (Germany); Univ. Grenoble Alpes-CEA-CNRS, Grenoble (France); Juelich Center for Structural Biology, Juelich (Germany); RWTH Aachen Univ., Aachen (Germany)
- Univ. of Southern California, Los Angeles, CA (United States). Center for Energy Nanoscience and Technology
- Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Inst. of Complex Systems, Juelich (Germany); Juelich Center for Structural Biology, Juelich (Germany)
- Moscow Inst. of Physics and Technology, Dolgoprudny (Russia); Univ. of Southern California, Los Angeles, CA (United States)
- Publication Date:
- Research Org.:
- SLAC National Accelerator Lab., Menlo Park, CA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1577320
- Grant/Contract Number:
- AC02-76SF00515; 1231306; R21 DA042298; R35 GM127086; R01 GM124152; FDN-148413; 18-02-40020; 16-14-10273
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science Advances
- Additional Journal Information:
- Journal Volume: 5; Journal Issue: 10; Journal ID: ISSN 2375-2548
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
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, and Cherezov, Vadim. Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. United States: N. p., 2019.
Web. doi:10.1126/sciadv.aax2518.
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. Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs. United States. https://doi.org/10.1126/sciadv.aax2518
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, and Cherezov, Vadim. Wed .
"Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs". United States. https://doi.org/10.1126/sciadv.aax2518. https://www.osti.gov/servlets/purl/1577320.
@article{osti_1577320,
title = {Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs},
author = {Luginina, Aleksandra and Gusach, Anastasiia and Marin, Egor and Mishin, Alexey and Brouillette, Rebecca and Popov, Petr and Shiriaeva, Anna and Besserer-Offroy, Élie and Longpré, Jean -Michel and Lyapina, Elizaveta and Ishchenko, Andrii and Patel, Nilkanth and Polovinkin, Vitaly and Safronova, Nadezhda and Bogorodskiy, Andrey and Edelweiss, Evelina and Hu, Hao and Weierstall, Uwe and Liu, Wei and Batyuk, Alexander and Gordeliy, Valentin and Han, Gye Won and Sarret, Philippe and Katritch, Vsevolod and Borshchevskiy, Valentin and Cherezov, Vadim},
abstractNote = {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 = {10.1126/sciadv.aax2518},
journal = {Science Advances},
number = 10,
volume = 5,
place = {United States},
year = {2019},
month = {10}
}
Web of Science
Works referenced in this record:
Cysteinyl leukotriene receptors, old and new; implications for asthma
journal, August 2012
- Laidlaw, T. M.; Boyce, J. A.
- Clinical & Experimental Allergy, Vol. 42, Issue 9
[19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors
book, January 1995
- Ballesteros, Juan A.; Weinstein, Harel
- Receptor Molecular Biology, Vol. 25, p. 366-428
The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints
journal, June 2003
- Fredriksson, Robert; Lagerström, Malin C.; Lundin, Lars-Gustav
- Molecular Pharmacology, Vol. 63, Issue 6
Cheetah : software for high-throughput reduction and analysis of serial femtosecond X-ray diffraction data
journal, May 2014
- Barty, Anton; Kirian, Richard A.; Maia, Filipe R. N. C.
- Journal of Applied Crystallography, Vol. 47, Issue 3
CrystFEL : a software suite for snapshot serial crystallography
journal, March 2012
- White, Thomas A.; Kirian, Richard A.; Martin, Andrew V.
- Journal of Applied Crystallography, Vol. 45, Issue 2
High-resolution crystal structure of human protease-activated receptor 1
journal, December 2012
- Zhang, Cheng; Srinivasan, Yoga; Arlow, Daniel H.
- Nature, Vol. 492, Issue 7429
Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1
journal, January 2018
- Hori, Tetsuya; Okuno, Toshiaki; Hirata, Kunio
- Nature Chemical Biology, Vol. 14, Issue 3
Agonist-bound structure of the human P2Y12 receptor
journal, April 2014
- Zhang, Jin; Zhang, Kaihua; Gao, Zhan-Guo
- Nature, Vol. 509, Issue 7498
Cellular signalling of cysteinyl leukotriene type 1 receptor variants CysLT1-G300S and CysLT1-I206S
journal, February 2016
- Yaddaden, Louiza; Véronneau, Steeve; Thompson, Miles D.
- Prostaglandins, Leukotrienes and Essential Fatty Acids, Vol. 105
Accurate determination of segmented X-ray detector geometry
journal, January 2015
- Yefanov, Oleksandr; Mariani, Valerio; Gati, Cornelius
- Optics Express, Vol. 23, Issue 22
High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875
journal, July 2014
- Srivastava, Ankita; Yano, Jason; Hirozane, Yoshihiko
- Nature, Vol. 513, Issue 7516
Neuropsychiatric Events Associated with Leukotriene-Modifying Agents: A Systematic Review
journal, October 2017
- Law, Sharon W. Y.; Wong, Angel Y. S.; Anand, Shweta
- Drug Safety, Vol. 41, Issue 3
Structural basis for signal recognition and transduction by platelet-activating-factor receptor
journal, May 2018
- Cao, Can; Tan, Qiuxiang; Xu, Chanjuan
- Nature Structural & Molecular Biology, Vol. 25, Issue 6
Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6
journal, August 2017
- Taniguchi, Reiya; Inoue, Asuka; Sayama, Misa
- Nature, Vol. 548, Issue 7667
Opiate Agonists and Antagonists Discriminated by Receptor Binding in Brain
journal, December 1973
- Pert, C. B.; Pasternak, G.; Snyder, S. H.
- Science, Vol. 182, Issue 4119
Structural basis for selectivity and diversity in angiotensin II receptors
journal, April 2017
- Zhang, Haitao; Han, Gye Won; Batyuk, Alexander
- Nature, Vol. 544, Issue 7650
Churg-Strauss syndrome and the leukotriene receptor antagonist pranlukast
journal, December 2004
- Shimbo, Junsuke; Onodera, Osamu; Tanaka, Keiko
- Clinical Rheumatology, Vol. 24, Issue 6
Fusion Partner Toolchest for the Stabilization and Crystallization of G Protein-Coupled Receptors
journal, June 2012
- Chun, Eugene; Thompson, Aaron A.; Liu, Wei
- Structure, Vol. 20, Issue 6
GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
journal, September 2015
- Abraham, Mark James; Murtola, Teemu; Schulz, Roland
- SoftwareX, Vol. 1-2
Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions
journal, July 2012
- Liu, W.; Chun, E.; Thompson, A. A.
- Science, Vol. 337, Issue 6091
OPM database and PPM web server: resources for positioning of proteins in membranes
journal, September 2011
- Lomize, Mikhail A.; Pogozheva, Irina D.; Joo, Hyeon
- Nucleic Acids Research, Vol. 40, Issue D1
A functional G300S variant of the cysteinyl leukotriene 1 receptor is associated with atopy in a Tristan da Cunha isolate
journal, January 2007
- Thompson, Miles D.; Capra, Valérie; Takasaki, Jun
- Pharmacogenetics and Genomics, Vol. 17, Issue 7
Microscale Fluorescent Thermal Stability Assay for Membrane Proteins
journal, March 2008
- Alexandrov, Alexander I.; Mileni, Mauro; Chien, Ellen Y. T.
- Structure, Vol. 16, Issue 3
Serial Femtosecond Crystallography of G Protein–Coupled Receptors
journal, May 2018
- Stauch, Benjamin; Cherezov, Vadim
- Annual Review of Biophysics, Vol. 47, Issue 1
Nationwide cohort study of the leukotriene receptor antagonist montelukast and incident or recurrent cardiovascular disease
journal, March 2012
- Ingelsson, Erik; Yin, Li; Bäck, Magnus
- Journal of Allergy and Clinical Immunology, Vol. 129, Issue 3
Crystallizing membrane proteins using lipidic mesophases
journal, April 2009
- Caffrey, Martin; Cherezov, Vadim
- Nature Protocols, Vol. 4, Issue 5
Characterization of the human cysteinyl leukotriene CysLT1 receptor
journal, June 1999
- Lynch, Kevin R.; O'Neill, Gary P.; Liu, Qingyun
- Nature, Vol. 399, Issue 6738
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
Structure-Function of the G Protein–Coupled Receptor Superfamily
journal, January 2013
- Katritch, Vsevolod; Cherezov, Vadim; Stevens, Raymond C.
- Annual Review of Pharmacology and Toxicology, Vol. 53, Issue 1
The application of hierarchical cluster analysis to the selection of isomorphous crystals
journal, May 2012
- Giordano, Rita; Leal, Ricardo M. F.; Bourenkov, Gleb P.
- Acta Crystallographica Section D Biological Crystallography, Vol. 68, Issue 6
Serial Femtosecond Crystallography of G Protein-Coupled Receptors
journal, December 2013
- Liu, W.; Wacker, D.; Gati, C.
- Science, Vol. 342, Issue 6165
Evaluation of Cysteinyl Leukotriene Signaling as a Therapeutic Target for Colorectal Cancer
journal, September 2016
- Burke, Lorraine; Butler, Clare T.; Murphy, Adrian
- Frontiers in Cell and Developmental Biology, Vol. 4
CHARMM-GUI: A web-based graphical user interface for CHARMM
journal, March 2008
- Jo, Sunhwan; Kim, Taehoon; Iyer, Vidyashankara G.
- Journal of Computational Chemistry, Vol. 29, Issue 11
Allosteric sodium in class A GPCR signaling
journal, May 2014
- Katritch, Vsevolod; Fenalti, Gustavo; Abola, Enrique E.
- Trends in Biochemical Sciences, Vol. 39, Issue 5
Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography
journal, February 2014
- Weierstall, Uwe; James, Daniel; Wang, Chong
- Nature Communications, Vol. 5, Issue 1
MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009
- Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1
Cysteinyl-Leukotriene Receptor Antagonists: Present Situation and Future Opportunities
journal, November 2006
- Capra, V.; Ambrosio, M.; Riccioni, G.
- Current Medicinal Chemistry, Vol. 13, Issue 26
Two disparate ligand-binding sites in the human P2Y1 receptor
journal, March 2015
- Zhang, Dandan; Gao, Zhan-Guo; Zhang, Kaihua
- Nature, Vol. 520, Issue 7547
Features and development of Coot
journal, March 2010
- Emsley, P.; Lohkamp, B.; Scott, W. G.
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
Sodium Ion Binding Pocket Mutations and Adenosine A 2A Receptor Function
journal, December 2014
- Massink, Arnault; Gutiérrez-de-Terán, Hugo; Lenselink, Eelke B.
- Molecular Pharmacology, Vol. 87, Issue 2
ICM?A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation
journal, May 1994
- Abagyan, Ruben; Totrov, Maxim; Kuznetsov, Dmitry
- Journal of Computational Chemistry, Vol. 15, Issue 5
A quantitative approach to data-collection strategies
journal, December 2005
- Bourenkov, Gleb P.; Popov, Alexander N.
- Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 1
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Cysteinyl-leukotrienes and their receptors in asthma and other inflammatory diseases: Critical update and emerging trends
journal, January 2007
- Capra, Valérie; Thompson, Miles D.; Sala, Angelo
- Medicinal Research Reviews, Vol. 27, Issue 4
Leukotriene C4 synthase gene A(-444)C polymorphism and clinical response to a CYS-LT1 antagonist, pranlukast, in Japanese patients with moderate asthma
journal, January 2002
- Asano, Koichiro; Shiomi, Tetsuya; Hasegawa, Naoki
- Pharmacogenetics, Vol. 12, Issue 7
Harnessing Ion-Binding Sites for GPCR Pharmacology
journal, September 2019
- Zarzycka, Barbara; Zaidi, Saheem A.; Roth, Bryan L.
- Pharmacological Reviews, Vol. 71, Issue 4
International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions
journal, July 2011
- Bäck, Magnus; Dahlén, Sven-Erik; Drazen, Jeffrey M.
- Pharmacological Reviews, Vol. 63, Issue 3
Evolutionary action and structural basis of the allosteric switch controlling β2AR functional selectivity
journal, December 2017
- Schönegge, Anne-Marie; Gallion, Jonathan; Picard, Louis-Philippe
- Nature Communications, Vol. 8, Issue 1
Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7: IUPHAR update on LT receptors
journal, July 2014
- Bäck, Magnus; Powell, William S.; Dahlén, Sven-Erik
- British Journal of Pharmacology, Vol. 171, Issue 15
Structural insight into allosteric modulation of protease-activated receptor 2
journal, April 2017
- Cheng, Robert K. Y.; Fiez-Vandal, Cédric; Schlenker, Oliver
- Nature, Vol. 545, Issue 7652
Crystal Structure of a Lipid G Protein-Coupled Receptor
journal, February 2012
- Hanson, M. A.; Roth, C. B.; Jo, E.
- Science, Vol. 335, Issue 6070
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
Exploring the gas access routes in a [NiFeSe] hydrogenase using crystals pressurized with krypton and oxygen
journal, August 2020
- Zacarias, Sónia; Temporão, Adriana; Carpentier, Philippe
- JBIC Journal of Biological Inorganic Chemistry, Vol. 25, Issue 6
PARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
journal, December 2019
- Sharma, Deepti; De Falco, Louis; Padavattan, Sivaraman
- Nature Communications, Vol. 10, Issue 1
Human aminolevulinate synthase structure reveals a eukaryotic-specific autoinhibitory loop regulating substrate binding and product release
journal, June 2020
- Bailey, Henry J.; Bezerra, Gustavo A.; Marcero, Jason R.
- Nature Communications, Vol. 11, Issue 1
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021
- Tillu, Vikas A.; Rae, James; Gao, Ya
- Nature Communications, Vol. 12, Issue 1
Rational identification and characterisation of peptide ligands for targeting polysialic acid
journal, May 2020
- Shastry, Divya G.; Irudayanathan, Flaviyan Jerome; Williams, Asher
- Scientific Reports, Vol. 10, Issue 1
Cysteinyl-Leukotrienes and Their Receptors in Asthma and Other Inflammatory Diseases: Critical Update and Emerging Trends
journal, September 2007
- Capra, Valerie; Thompson, Miles D.; Sala, Angelo
- ChemInform, Vol. 38, Issue 39
Accurate determination of segmented X-ray detector geometry
text, January 2015
- Yefanov, Oleksandr; Mariani, Valerio; Gati, Cornelius
- Deutsches Elektronen-Synchrotron, DESY, Hamburg
Allosteric sodium in class A GPCR signaling
text, January 2014
- Vsevolod, Katritch,; Vadim, Cherezov,; C., Stevens, Raymond
- The University of North Carolina at Chapel Hill University Libraries
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
Works referencing / citing this record:
Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors
journal, December 2019
- Gusach, Anastasiia; Luginina, Aleksandra; Marin, Egor
- Nature Communications, Vol. 10, Issue 1
Structural insights into melatonin receptors
journal, November 2019
- Stauch, Benjamin; Johansson, Linda C.; Cherezov, Vadim
- The FEBS Journal, Vol. 287, Issue 8
Raman Scattering: From Structural Biology to Medical Applications
journal, January 2020
- Vlasov, Alexey V.; Maliar, Nina L.; Bazhenov, Sergey V.
- Crystals, Vol. 10, Issue 1
Raman Scattering: From Structural Biology to Medical Applications
text, January 2020
- Vlasov, Alexey V.; Maliar, Nina L.; Bazhenov, Sergey V.
- RWTH Aachen University
Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors
text, January 2019
- Gusach, Anastasiia; Luginina, Aleksandra; Marin, Egor
- RWTH Aachen University