Figure 2, Structural dynamics of class C GPCR ligand binding domains (LBDs).

A, LBD dimers (dashed box) initiate activation following binding to orthosteric ligands, as shown in the full-length mGluR5 structure. B, Summary of mGluR LBD conformational changes. In an apo structure of mGluR1 (left) LBDs are found in the “open” state with upper (LB1) and lower (LB2) lobes far apart. At the inter-subunit level this structure is characterized as “relaxed” due to the lack of an inter-LBD interface. In a glutamate-bound structure of mGluR2 (right) both LBDs are in the closed state and dimer reorientation has allowed for the formation of an electrostatic LBD interface to form the “active state”. Note that the O-O/R and C-C/A are thought of as extreme conformations, that many intermediates exist and that the correlation between ligand occupancy and conformation is complex. C, 6-state model of mGluR LBD activation incorporating intra-subunit and inter-subunit conformational changes. * indicates states that have been captured in crystal structures. A 3-state model based on smFRET studies is highlighted with donor and acceptor fluorophore positions shown as green and red ovals. Right, representative smFRET trace showing the transition of mGluR2 between three states (dotted lines) on tens of ms time scale at approximately EC ₅₀ glutamate levels. Inset shows the relative occupancy of the C-C/A state observed for mGluR2 under different conditions. D, Free energy diagrams summarizing differences in relative stability of relaxed and active states for mGluR2, 3 and 7. mGluR3 shows basal occupancy of the active state while mGluR7 shows minimal occupancy of the active state, even under saturating agonist conditions. E, GABA_BR LBD dimer structures showing a comparatively subtle dimer reorientation associated with activation.