1. Neuroscience
  2. Structural Biology and Molecular Biophysics
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Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor

  1. Vanessa A Gutzeit
  2. Jordana Thibado
  3. Daniel Starer Stor
  4. Zhou Zhou
  5. Scott C Blanchard
  6. Olaf S Andersen
  7. Joshua Levitz  Is a corresponding author
  1. Weill Cornell Graduate School of Medical Sciences, United States
  2. Weill Cornell Medicine, United States
Research Article
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Cite this article as: eLife 2019;8:e45116 doi: 10.7554/eLife.45116

Abstract

Metabotropic glutamate receptors (mGluRs) are class C, synaptic G protein-coupled receptors (GPCRs) that contain large extracellular ligand binding domains (LBDs) and form constitutive dimers. Despite the existence of a detailed picture of inter-LBD conformational dynamics and structural snapshots of both isolated domains and full-length receptors, it remains unclear how mGluR activation proceeds at the level of the transmembrane domains (TMDs) and how TMD-targeting allosteric drugs exert their effects. Here we use time-resolved functional and conformational assays to dissect the mechanisms by which allosteric drugs activate and modulate mGluR2. Single-molecule subunit counting and inter-TMD fluorescence resonance energy transfer measurements in living cells reveal LBD-independent conformational rearrangements between TMD dimers during receptor modulation. Using these assays along with functional readouts, we uncover heterogeneity in the magnitude, direction, and the timing of the action of both positive and negative allosteric drugs. Together our experiments lead to a 3-state model of TMD activation, which provides a framework for understanding how inter-subunit rearrangements drive class C GPCR activation.

Article and author information

Author details

  1. Vanessa A Gutzeit

    Neuroscience Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    Competing interests
    No competing interests declared.
  2. Jordana Thibado

    Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    Competing interests
    No competing interests declared.
  3. Daniel Starer Stor

    Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    Competing interests
    No competing interests declared.
  4. Zhou Zhou

    Department of Physiology and Biophysics, Weill Cornell Medicine, New York, United States
    Competing interests
    No competing interests declared.
  5. Scott C Blanchard

    Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    Competing interests
    Scott C Blanchard, SCB holds equity interest in Lumidyne Technologies.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2717-9365
  6. Olaf S Andersen

    Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    Competing interests
    No competing interests declared.
  7. Joshua Levitz

    Physiology, Biophysics and Systems Biology Graduate Program, Weill Cornell Graduate School of Medical Sciences, New York, United States
    For correspondence
    jtl2003@med.cornell.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8169-6323

Funding

National Institute of General Medical Sciences (1R35GM124731)

  • Joshua Levitz

National Institute of General Medical Sciences (1R01GM021342)

  • Olaf S Andersen

National Institute of General Medical Sciences (R01GM098858-07)

  • Scott C Blanchard

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

Reviewing Editor

  1. Kenton Jon Swartz, National Institute of Neurological Disorders and Stroke, National Institutes of Health, United States

Publication history

  1. Received: January 11, 2019
  2. Accepted: June 6, 2019
  3. Accepted Manuscript published: June 7, 2019 (version 1)

Copyright

© 2019, Gutzeit et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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