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 CysLT ₁R mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLT ₁R 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 ₁R 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.

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                    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.

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                    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.

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@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}

}

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DOI: 10.1126/sciadv.aax2518

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

Abstract

Citation Formats

Fusion Partner Toolchest for the Stabilization and Crystallization of G Protein-Coupled Receptors journal, June 2012

Crystallizing membrane proteins using lipidic mesophases journal, April 2009

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

Structure-Function of the G Protein–Coupled Receptor Superfamily journal, January 2013

Allosteric sodium in class A GPCR signaling journal, May 2014

The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints journal, June 2003

Two disparate ligand-binding sites in the human P2Y1 receptor journal, March 2015

Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions journal, July 2012

High-resolution crystal structure of human protease-activated receptor 1 journal, December 2012

High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875 journal, July 2014

Crystal Structure of a Lipid G Protein-Coupled Receptor journal, February 2012

Microscale Fluorescent Thermal Stability Assay for Membrane Proteins journal, March 2008

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

XDS journal, January 2010

The application of hierarchical cluster analysis to the selection of isomorphous crystals journal, May 2012

Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography journal, February 2014

Cheetah : software for high-throughput reduction and analysis of serial femtosecond X-ray diffraction data journal, May 2014

CrystFEL : a software suite for snapshot serial crystallography journal, March 2012

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

Phaser crystallographic software journal, July 2007

Features and development of Coot journal, March 2010

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal, January 2010

ICM?A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation journal, May 1994

Structural basis for selectivity and diversity in angiotensin II receptors journal, April 2017

CHARMM-GUI: A web-based graphical user interface for CHARMM journal, March 2008

OPM database and PPM web server: resources for positioning of proteins in membranes journal, September 2011

GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers journal, September 2015

MolProbity : all-atom structure validation for macromolecular crystallography journal, December 2009

Fusion Partner Toolchest for the Stabilization and Crystallization of G Protein-Coupled Receptors
journal, June 2012

Crystallizing membrane proteins using lipidic mesophases
journal, April 2009

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

Structure-Function of the G Protein–Coupled Receptor Superfamily
journal, January 2013

Allosteric sodium in class A GPCR signaling
journal, May 2014

The G-Protein-Coupled Receptors in the Human Genome Form Five Main Families. Phylogenetic Analysis, Paralogon Groups, and Fingerprints
journal, June 2003

Two disparate ligand-binding sites in the human P2Y1 receptor
journal, March 2015

Structural Basis for Allosteric Regulation of GPCRs by Sodium Ions
journal, July 2012

High-resolution crystal structure of human protease-activated receptor 1
journal, December 2012

High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875
journal, July 2014

Crystal Structure of a Lipid G Protein-Coupled Receptor
journal, February 2012

Microscale Fluorescent Thermal Stability Assay for Membrane Proteins
journal, March 2008

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

XDS
journal, January 2010

The application of hierarchical cluster analysis to the selection of isomorphous crystals
journal, May 2012

Lipidic cubic phase injector facilitates membrane protein serial femtosecond crystallography
journal, February 2014

Cheetah : software for high-throughput reduction and analysis of serial femtosecond X-ray diffraction data
journal, May 2014

CrystFEL : a software suite for snapshot serial crystallography
journal, March 2012

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

Phaser crystallographic software
journal, July 2007

Features and development of Coot
journal, March 2010

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

ICM?A new method for protein modeling and design: Applications to docking and structure prediction from the distorted native conformation
journal, May 1994

Structural basis for selectivity and diversity in angiotensin II receptors
journal, April 2017

CHARMM-GUI: A web-based graphical user interface for CHARMM
journal, March 2008

OPM database and PPM web server: resources for positioning of proteins in membranes
journal, September 2011

GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers
journal, September 2015

MolProbity : all-atom structure validation for macromolecular crystallography
journal, December 2009