Fig. 5: Antagonist-bound structures of mGluR3 reveal dynamic inter-CRD positioning, intra-TMD reorganization, and multiple TM3/4/5 inter-TMD interfaces.

a Full-length cryo-EM density maps and protein model, when applicable, for LY341495 (antagonist; LY34) and LY34/VU6023326 (antagonist/PAM; LY34/VU602) bound mGluR3. LY34 class 2 and LY34/VU602 class 1 density maps are depicted with a low pass filter of 6 Å. b Plot comparing inter-LB2 versus inter-CRD distance across reported antagonist and or NAM-bound homodimeric mGluR subtypes measured via conserved positions as in Fig. 5b. c LY34 class 1 (gold), LY34 class 3 (raspberry) and LY34/VU602 class 2 (lavender) structures aligned via the top lobe (LB1) of chain A. Structural offsets are reported for residues, R206 (4.4 Å and 1.1 Å), I530 (8.3 Å and 2.7 Å), and P566 (21.5 Å and 5.8 Å). d, e TMD alignments between LY34 class 3 and LY34/VU602 class 2 structures with offsets highlighted by red arrows. Alignments are performed for the entire TMD from residue 571 to the end of the model, including loops. f TMD alignments between LY34/VU602 class 2, LY37/VU602, and agonist/PAM/G protein-bound mGluR2 (PDB: 7TMS) structures showing subtle differences in TM1, TM6, and TM7 positioning. g Top view of TMDs with inter-TMD distance measured from the alpha carbon of Cα V639 (TM3) and I708 (TM4) for LY34 class 1 and between V746 (TM5) for LY34 class 3 and LY34/VU602 class 2. h Inter-TM5 interface profile measured by intersubunit C\(\alpha\) distance of outward facing residues for LY34 class 3 and LY34/VU602 class 2. i Plot of inter-TM5 distance across full length homodimeric mGluR structures using a conserved TM5 position (y-axis) and the center of mass distance of the TMD bundles (x-axis).