Conformational fingerprinting of allosteric modulators in metabotropic glutamate receptor 2

Brandon Wey-Hung Liauw, Arash Foroutan, Michael Schamber, Weifeng Lu, Hamid Samareh Afsari*, Reza Vafabakhsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Activation of G protein-coupled receptors (GPCRs) is an allosteric process. It involves conformational coupling between the orthosteric ligand binding site and the G protein binding site. Factors that bind at non-cognate ligand binding sites to alter the allosteric activation process are classified as allosteric modulators and represent a promising class of therapeutics with distinct modes of binding and action. For many receptors, how modulation of signaling is represented at the structural level is unclear. Here, we developed FRET sensors to quantify receptor modulation at each of the three structural domains of metabotropic glutamate receptor 2 (mGluR2). We identified the conformational fingerprint for several allosteric modulators in live cells. This approach enabled us to derive a receptor-centric representation of allosteric modulation and to correlate structural modulation to the standard signaling modulation metrics. Single-molecule FRET analysis revealed that a NAM increases the occupancy of one of the intermediate states while a PAM increases the occupancy of the active state. Moreover, we found that the effect of allosteric modulators on the receptor dynamics is complex and depend on the orthosteric ligand. Collectively, our findings provide a structural mechanism of allosteric modulation in mGluR2 and suggest possible strategies for design of future modulators.

Original languageEnglish (US)
Article numbere78982
JournaleLife
Volume11
DOIs
StatePublished - Jul 2022

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Neuroscience

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