Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor
- Weill Cornell Graduate School of Medical Sciences, United States
- Weill Cornell Medicine, United States
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
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.
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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Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor
eLife 8:e45116.
https://doi.org/10.7554/eLife.45116
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