Fig. 7

Cross-linked S729C LBD structures suggest a model of gating for desensitized GluA2(R). a Left, crystal structure of the dimeric GluA2 S729C ligand-binding core in the presence of NBQX, with the upper (D1, pale) and lower (D2, dark) lobes of each monomer (red and blue) distinguished by shading. The structure is viewed perpendicular to the axis between the Cα atoms of Pro632 (magenta spheres). Right, crystal structure of the GluA2 S729C ligand-binding core in the presence of glutamate (S729C_glu; PDB: 2I3W)¹⁸. The Pro632 separation seen in the presence of glutamate (right) is >3 Å greater than that seen with NBQX (left). b Cartoon representing possible conformations of the GluA2(R) LBD dimer and pore in our functional cross-linking recordings. Non-cross-linked GluA2(R) channels bind glutamate (gray spheres), closing the clamshell LBDs and opening the pore to the full open channel conductance. Desensitization does not fully close the pore. As determined in the presence of γ-2, cross-linking of the G724C mutant (yellow) does not allow the action of agonist binding to be communicated to the pore in any state, and disrupts the normal dimeric conformation of desensitized receptors. Cross-linking of the S729C mutant (yellow) is not compatible with the full open state, but the channel can adopt the normal desensitized conformation, meaning that (as with the non-cross-linked receptor) the pore is not closed