Extended Data Figure 4. Inhibition of GluK2_EM by LY466195 and LBD crystal structures for agonist and antagonist complexes.

a, Crystal structure for the GluK2_EM isolated LBD dimer assembly complex with 2S,4R-4-methylglutamate; the upper/lower lobes for the two subunits are colored orange/pale yellow and teal/pale cyan respectively; the dashed line indicates the separation of the lower lobes measured as the distance between the Cα positions of Ile637. b, Crystal structure for the GluK2_EM isolated LBD dimer assembly complex with LY466195 illustrating the large decrease in separation of the lower lobes compared to the agonist complex. Coloring is the same as in (a). c, Responses to 100 μM glutamate recorded under two electrode voltage clamp for GluK2_EM (top) and wild type GluK2 (bottom); the initial response to glutamate recorded after prior application of 300 nM LY466195 showed nearly complete block for GluK2_EM with no change in amplitude for wild type. d, Concentration dependence for inhibition of GluK2_EM by LY466195 yielded an IC₅₀ of 30 nM.