Illuminating the activation mechanisms and allosteric properties of metabotropic glutamate receptors

E Doumazane, P Scholler, L Fabre… - Proceedings of the …, 2013 - National Acad Sciences
E Doumazane, P Scholler, L Fabre, JM Zwier, E Trinquet, JP Pin, P Rondard
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-
binding domains (ECDs) associated with receptor activation remain largely unknown. This is
the case for the dimeric metabotropic glutamate receptors even though a number of ECD
structures have been solved. Here, using an innovative approach based on cell-surface
labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with
receptor and G-protein activation. Our approach helps identify partial agonists and highlights …
In multimeric cell-surface receptors, the conformational changes of the extracellular ligand-binding domains (ECDs) associated with receptor activation remain largely unknown. This is the case for the dimeric metabotropic glutamate receptors even though a number of ECD structures have been solved. Here, using an innovative approach based on cell-surface labeling and FRET, we demonstrate that a reorientation of the ECDs is associated with receptor and G-protein activation. Our approach helps identify partial agonists and highlights allosteric interactions between the effector and binding domains. Any approach expected to stabilize the active conformation of the effector domain increased the agonist potency in stabilizing the active ECDs conformation. These data provide key information on the structural dynamics and drug action at metabotropic glutamate receptors and validate an approach for tackling such analysis on other receptors.
National Acad Sciences