1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics
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Distinct inactive conformations of the dopamine D2 and D3 receptors correspond to different extents of inverse agonism

  1. J Robert Lane  Is a corresponding author
  2. Ara M Abramyan
  3. Pramisha Adhikari
  4. Alastair C Keen
  5. Kuo-Hao Lee
  6. Julie Sanchez
  7. Ravi Kumar Verma
  8. Herman D Lim
  9. Hideaki Yano
  10. Jonathan A Javitch  Is a corresponding author
  11. Lei Shi  Is a corresponding author
  1. University of Nottingham, United Kingdom
  2. National Institute on Drug Abuse, National Institutes of Health, United States
  3. Monash University, Australia
  4. Columbia University, United States
Research Article
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Cite this article as: eLife 2020;9:e52189 doi: 10.7554/eLife.52189

Abstract

By analyzing and simulating inactive conformations of the highly-homologous dopamine D2 and D3 receptors (D2R and D3R), we find that eticlopride binds D2R in a pose very similar to that in the D3R/eticlopride structure but incompatible with the D2R/risperidone structure. In addition, risperidone occupies a sub-pocket near the Na+ binding site, whereas eticlopride does not. Based on these findings and our experimental results, we propose that the divergent receptor conformations stabilized by Na+-sensitive eticlopride and Na+-insensitive risperidone correspond to different degrees of inverse agonism. Moreover, our simulations reveal that the extracellular loops are highly dynamic, with spontaneous transitions of extracellular loop 2 from the helical conformation in the D2R/risperidone structure to an extended conformation similar to that in the D3R/eticlopride structure. Our results reveal previously unappreciated diversity and dynamics in the inactive conformations of D2R. These findings are critical for rational drug discovery, as limiting a virtual screen to a single conformation will miss relevant ligands.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

  1. J Robert Lane

    Division of Pharmacology, Physiology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
    For correspondence
    Rob.Lane@nottingham.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Ara M Abramyan

    Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Pramisha Adhikari

    Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Alastair C Keen

    Division of Pharmacology, Physiology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Kuo-Hao Lee

    Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Julie Sanchez

    Division of Pharmacology, Physiology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Ravi Kumar Verma

    Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Herman D Lim

    Department of Pharmacology and Medicinal Chemistry, Monash University, Parkville, Australia
    Competing interests
    The authors declare that no competing interests exist.
  9. Hideaki Yano

    Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jonathan A Javitch

    Department of Psychiatry, Columbia University, New York, United States
    For correspondence
    jaj2@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
  11. Lei Shi

    Computational Chemistry and Molecular Biophysics Unit, National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
    For correspondence
    lei.shi2@nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4137-096X

Funding

National Institutes of Health (Z1A DA000606-03)

  • Lei Shi

National Institutes of Health (MH54137)

  • Jonathan A Javitch

National Health and Medical Research Council (APP1049564)

  • J Robert Lane

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Publication history

  1. Received: September 25, 2019
  2. Accepted: January 24, 2020
  3. Accepted Manuscript published: January 27, 2020 (version 1)
  4. Version of Record published: March 3, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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