Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor

Laura Pérez-Benito, Maarten L.J. Doornbos, Arnau Cordomí, Luc Peeters, Hilde Lavreysen, Leonardo Pardo, Gary Tresadern

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

© 2017 Elsevier Ltd Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) crucial for CNS function and important drug discovery targets. Glutamate triggers receptor activation from an extracellular domain binding site while allosteric modulators bind in the seven-transmembrane domain. Little is known about how allosteric modulators produce their functional effects at the molecular level. Here we address this topic with combined experimental and computational approaches and reveal that mGlu receptor allosteric modulators interact with the homologous “trigger switch” and “transmission switch” amino acids as seen in class A GPCRs, in short, the characteristic hallmarks of class A agonist activation translate to the mGlu allosteric modulator. The proposed “trigger switch” for the mGlu2 involves the side chains of F6433.36a.40c, N7355.47a.47c, and W7736.48a.50c, whereas the “transmission switch” involves the Y6473.40a.44c, L7385.50a.50c, and T7696.44a.46c amino acids. The work has wide impact on understanding mGlu GPCR function and for future allosteric modulator drugs.
Original languageEnglish
Pages (from-to)1153-1162.e4
JournalStructure
Volume25
Issue number7
DOIs
Publication statusPublished - 5 Jul 2017

Keywords

  • GPCR
  • NAM
  • PAM
  • activation
  • allosteric modulator
  • class C
  • mGlu
  • mGluR
  • molecular dynamics
  • transmission switch

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