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Nathalie Lecat-Guillet1, Robert B Quast2, Hongkang Liu1,3

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Allosteric modulators fine-tune neurotransmitter action by controlling metabotropic glutamate (mGlu) receptor activity. These ligands stabilize the fully active dimer conformation of mGlu2 receptors, crucial for brain function.

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Area of Science:

  • Neuroscience
  • Biochemistry
  • Molecular Biology

Background:

  • Metabotropic glutamate (mGlu) receptors are key regulators of neurotransmission and implicated in brain disorders.
  • Allosteric modulators offer precise control over receptor activity by interacting with distinct sites.
  • Understanding ligand-induced conformational changes is vital for drug development.

Purpose of the Study:

  • To investigate the single-molecule conformational dynamics of full-length mGlu2 receptors upon orthosteric and allosteric ligand binding.
  • To elucidate the synergistic roles of orthosteric and allosteric ligands in modulating receptor activity.

Main Methods:

  • Development of Förster Resonance Energy Transfer (FRET) sensors using genetic code expansion and click chemistry for live-cell monitoring.
  • Application of single-molecule FRET to analyze conformational changes in mGlu2 receptors.

Main Results:

  • Orthosteric agonist binding partially stabilizes the closed state of glutamate binding domains but does not fully reorient the dimer to the active state.
  • Allosteric modulators binding to the transmembrane domain are essential for stabilizing the fully reoriented, active dimer conformation.
  • Concerted conformational changes within the multidomain dimeric GPCR are critical for its function.

Conclusions:

  • Allosteric modulators play a crucial role in achieving the fully active conformation of mGlu2 receptors.
  • The study provides insights into how multidomain protein conformational dynamics are controlled and modulated by ligands.
  • Findings highlight the therapeutic potential of allosteric modulators for brain diseases linked to mGlu receptors.