Fig. 3: Mechanism of allosteric inhibition.
From: Allosteric competition and inhibition in AMPA receptors
a, Overlay of the allosterically inhibited state (orange/purple) and the activated state (white, PDB 5WEO; activated with 1 mM Glu + 100 μM CTZ). Inset: Close-up view of the GYKI-52466-binding site, revealing a steric clash with the kinked M3 helix found in the open state. b, Overlay of isolated LBD clamshells from the allosterically inhibited state (pink) and the open state (white). c, Local clamshell dimers within the LBD layer viewed from behind, showing the relative distances of the D1 and D2 lobes of the LBD dimer, as illustrated by the landmark residues Ser741 (D1) and Ser635 (D2). d, Plot of the D1 distance (Cα of Ser741) versus D2 distance (Cα of Ser635) measured for representative AMPAR structures captured in the resting, activated or desensitized state. On the basis of these measurements, the allosterically inhibited states (pink) cluster most closely with the desensitized state structures. e, Overlay of the overall LBD layer of the inhibited state (pink), activated state (white, PDB 5WEO) and desensitized state (blue, PDB 5VHZ) viewed from the top or extracellular side. Movements are measured within LBD dimers and mapped into the tetramer. The black oval marks the symmetry axis. Desensitization causes a 14° clockwise rotation of the A and C subunits within the LBD layer relative to the activated state18. In contrast, allosteric inhibition drives a counterclockwise rotation of the B and D subunits within the LBD layer relative to the active state.
