Conformational dynamics between transmembrane domains and allosteric modulation of a metabotropic glutamate receptor

• DOI: 10.7554/elife.45116
• Publication Date: 2019-06-07T12:00:25Z
• Authors: Vanessa A Gutzeit; Jordana Thibado; Daniel Starer Stor; Zhou Zhou; Scott C Blanchard; Olaf S Andersen; Joshua Levitz
• Keywords: 0301 basic medicine; Intravital Microscopy; glutamate receptor; QH301-705.5; Protein Conformation; conformational dynamics; Science; Q; R; Receptors, Metabotropic Glutamate; GPCRs; 03 medical and health sciences; Allosteric Regulation; Fluorescence Resonance Energy Transfer; Medicine; Biology (General); Neuroscience

Metabotropic glutamate receptors (mGluRs) are class C, synaptic G-protein-coupled (GPCRs) that contain large extracellular ligand binding domains (LBDs) and form constitutive dimers. Despite the existence of a detailed picture inter-LBD conformational dynamics structural snapshots both isolated full-length receptors, it remains unclear how mGluR activation proceeds at level transmembrane (TMDs) TMD-targeting allosteric drugs exert their effects. Here, we use time-resolved functional assays to dissect mechanisms by which activate modulate mGluR2. Single-molecule subunit counting inter-TMD fluorescence resonance energy transfer measurements in living cells reveal LBD-independent rearrangements between TMD dimers during receptor modulation. Using these along with readouts, uncover heterogeneity magnitude, direction, timing action positive negative drugs. Together our experiments lead three-state model activation, provides framework for understanding inter-subunit drive C GPCR activation.