Fig. 18.

The mechanism linking agonist binding to channel opening at the M3 gate. (A) Structure of GluA2 AMPA receptor illustrates the different subunit positions within the tetramer, termed A/C (occupied by GluN1 in NMDA receptors, blue) and B/D (occupied by GluN2, gray). The green arrows illustrate the glutamate binding site within the bilobed, clamshell-like ABD (PDB: 5WEK). (B₁) Clamshell arrangement of an ABD dimer (left) and the two A/C (middle) and B/D (right) ABDs bound to glutamate, which produces clamshell closure. (B₂) The left panel shows resting arrangement of the M3-S2 linkers and the M3/M2 membrane regions, which form the core of the ion permeation pathway. M1 and M4 transmembrane helices are omitted for clarity. The middle panel illustrates how agonist binding repositions the M3 helices of the A/C subunits, with a movement vertically displaced (red) distal to the extracellular surface of the membrane. The right panel illustrates how glutamate binding to the B/D subunits laterally displaces the M3 helices (red), causing a splaying at the Ala within the SYTANLAAF conserved motif. (B₃) View of the extracellular side of the ion channel down the axis of the permeation path for closed (PDB: 5WEK) and open receptors (PDB: 5WEO). The side chains of Thr625, which form part of M3 activation gate, are shown.