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

doi:10.1126/sciadv.aax2518

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.

Authors:

^[1];

^[2]; Popov, Petr ^[3]; Shiriaeva, Anna ^[4];

^[2];

^[1]; Ishchenko, Andrii ^[5];

^[4];

^[6];

^[1]; Bogorodskiy, Andrey ^[1]; Edelweiss, Evelina ^[7];

^[8];

^[8]; Liu, Wei ^[8];

^[9] 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:: 2019-10-09

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.

Copy to clipboard


                    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.  doi:10.1126/sciadv.aax2518.

Copy to clipboard


                    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.  doi:10.1126/sciadv.aax2518.  https://www.osti.gov/servlets/purl/1577320.

Copy to clipboard


                    
@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}

}

Copy to clipboard

Journal Article:

Free Publicly Available Full Text

Accepted Manuscript (DOE)

Publisher's Version of Record

DOI: 10.1126/sciadv.aax2518

Other availability

Search WorldCat to find libraries that may hold this journal

Citation Metrics:

Cited by: 7 works

Citation information provided by
Web of Science

Save / Share:

Export Metadata

Save to My Library

Works referenced in this record:

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
DOI: 10.1124/pr.110.004184

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
DOI: 10.1038/21658

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
DOI: 10.1111/bph.12665

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
DOI: 10.3389/fcell.2016.00103

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
DOI: 10.1016/j.jaci.2011.11.052

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
DOI: 10.1111/j.1365-2222.2012.03982.x

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
DOI: 10.1002/med.20071

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
DOI: 10.2174/092986706778742963

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
DOI: 10.1097/00008571-200210000-00009

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
DOI: 10.1007/s40264-017-0607-1

Churg-Strauss syndrome and the leukotriene receptor antagonist pranlukast
journal, December 2004

Shimbo, Junsuke; Onodera, Osamu; Tanaka, Keiko
Clinical Rheumatology, Vol. 24, Issue 6
DOI: 10.1007/s10067-004-1035-z

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
DOI: 10.1016/j.str.2012.04.010

Crystallizing membrane proteins using lipidic mesophases
journal, April 2009

Caffrey, Martin; Cherezov, Vadim
Nature Protocols, Vol. 4, Issue 5
DOI: 10.1038/nprot.2009.31

Serial Femtosecond Crystallography of G Protein–Coupled Receptors
journal, May 2018

Stauch, Benjamin; Cherezov, Vadim
Annual Review of Biophysics, Vol. 47, Issue 1
DOI: 10.1146/annurev-biophys-070317-033239

[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
DOI: 10.1016/S1043-9471(05)80049-7

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
DOI: 10.1097/FPC.0b013e328012d0bf

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
DOI: 10.1016/j.plefa.2015.12.004

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
DOI: 10.1146/annurev-pharmtox-032112-135923

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
DOI: 10.1038/s41467-017-02257-x

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
DOI: 10.1016/j.tibs.2014.03.002

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
DOI: 10.1124/mol.114.095737

Harnessing Ion-Binding Sites for GPCR Pharmacology
journal, September 2019

Zarzycka, Barbara; Zaidi, Saheem A.; Roth, Bryan L.
Pharmacological Reviews, Vol. 71, Issue 4
DOI: 10.1124/pr.119.017863

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
DOI: 10.1124/mol.63.6.1256

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
DOI: 10.1038/nature14287

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
DOI: 10.1038/nchembio.2547

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
DOI: 10.1126/science.182.4119.1359

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
DOI: 10.1126/science.1219218

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
DOI: 10.1038/nature11701

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
DOI: 10.1038/nature22309

Agonist-bound structure of the human P2Y12 receptor
journal, April 2014

Zhang, Jin; Zhang, Kaihua; Gao, Zhan-Guo
Nature, Vol. 509, Issue 7498
DOI: 10.1038/nature13288

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
DOI: 10.1038/nature13494

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
DOI: 10.1126/science.1215904

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
DOI: 10.1038/s41594-018-0068-y

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
DOI: 10.1038/nature23448

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
DOI: 10.1016/j.str.2008.02.004

Serial Femtosecond Crystallography of G Protein-Coupled Receptors
journal, December 2013

Liu, W.; Wacker, D.; Gati, C.
Science, Vol. 342, Issue 6165
DOI: 10.1126/science.1244142

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
DOI: 10.1107/S0907444905033998

XDS
journal, January 2010

Kabsch, Wolfgang
Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
DOI: 10.1107/S0907444909047337

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
DOI: 10.1107/S0907444912006841

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
DOI: 10.1038/ncomms4309

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
DOI: 10.1107/S1600576714007626

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
DOI: 10.1107/S0021889812002312

Accurate determination of segmented X-ray detector geometry
journal, January 2015

Yefanov, Oleksandr; Mariani, Valerio; Gati, Cornelius
Optics Express, Vol. 23, Issue 22
DOI: 10.1364/OE.23.028459

Phaser crystallographic software
journal, July 2007

McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
Journal of Applied Crystallography, Vol. 40, Issue 4
DOI: 10.1107/S0021889807021206

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
DOI: 10.1107/S0907444910007493

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
DOI: 10.1107/S0907444909052925

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
DOI: 10.1002/jcc.540150503

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
DOI: 10.1038/nature22035

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
DOI: 10.1002/jcc.20945

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
DOI: 10.1093/nar/gkr703

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
DOI: 10.1016/j.softx.2015.06.001

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
DOI: 10.1107/S0907444909042073

Works referencing / citing this record: