Crystal structure of the GluK1 ligand-binding domain with kainate and the full-spanning positive allosteric modulator BPAM538

Kainate receptors play an important role in the central nervous system by mediating postsynaptic excitatory neurotransmission and modulating the release of the inhibitory neurotransmitter GABA through a presynaptic mechanism. To date, only three structures of the ligand-binding domain (LBD) of the kainate receptor subunit GluK1 in complex with positive allosteric modulators have been determined by X-ray crystallography, all belonging to class II modulators. Here, we report a high-resolution structure of GluK1-LBD in complex with kainate and BPAM538, which belongs to the full-spanning class III. One BPAM538 molecule binds at the GluK1 dimer interface, thereby occupying two allosteric binding sites simultaneously. BPAM538 stabilizes the active receptor conformation with only minor conformational changes being introduced to the receptor. Using a calcium-sensitive fluorescence-based assay, a 5-fold potentiation of the kainate response (100 M) was observed in the presence of 100 M BPAM538, whereas no potentiation was observed at GluK2. HighlightsO_LI1.9 [A] structure of the kainate receptor GluK1-LBD in complex with kainate and BPAM538 C_LIO_LIThe positive allosteric modulator BPAM538 occupies two binding sites C_LIO_LIThe binding mode is similar to class III modulators described for AMPA receptors C_LIO_LIBPAM538 prefers GluK1 over GluK2 C_LI