Fig. 6: Model for global activation of an mGluR homodimer.
a, smFRET data indicate that mGluR populates a series of discrete intermediates whose occupancy is affected by modulation of both the LBD and the TMD. States 1–3 correspond to inactive intermediates in which the LBD and CRD are relaxed with respect to each other. In states 4–6, the LBD adopts a twisted conformation, while CRDs differ in their proximity to one another. Gray bars indicate state occupancy under each ligand condition. b, Structural rendering of mGluR2 in its G protein-bound conformation—side chains highlighted in pink contribute to an intersubunit electrostatic network coordinated by R177; this network promotes LBD twisting. Helical region highlighted in blue undergoes additional protection in HDX-MS experiments upon binding of an allosteric modulator, providing a mechanism by which the TMD can modulate the LBD. c, Scatter plot of LBD–LBD (top) or TM6–TM6 (bottom) versus CRD–CRD distances across different full-length cryo-EM structures of mGluRs. A histogram of CRD–CRD distances reveals the heterogeneous spectrum of CRD–CRD distances observed across mGluR homodimers and heterodimers. Cα positions for Ala248 (mGluR2), Ala548 (mGluR2) or Phe756 (mGluR2), or the equivalent position in other mGluRs were used to determine LBD–LBD, CRD–CRD and TM6–TM6 distances, respectively.
