Molecular Switches of Allosteric Modulation of the Metabotropic Glutamate 2 Receptor

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 F643^3.36a.40c, N735^5.47a.47c, and W773^6.48a.50c, whereas the "transmission switch" involves the Y647^3.40a.44c, L738^5.50a.50c, and T769^6.44a.46c amino acids. The work has wide impact on understanding mGlu GPCR function and for future allosteric modulator drugs.