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Structure and affinity of two bicyclic glutamate analogues at AMPA and kainate receptors

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Stine Møllerud, Andrea Pinto, Laura Marconi, Karla Andrea Frydenvang, Thor Seneca Thorsen, Saara Kaisa Laulumaa, Raminta Venskutonyte, Nikolaj Winther, Ana Maria Cunado Moral, Lucia Tamborini, Paola Conti, Darryl S Pickering, Jette Sandholm Jensen Kastrup

Ionotropic glutamate receptors (iGluRs) are involved in most of the fast excitatory synaptic transmission in the central nervous system. These receptors are important for learning and memory formation, but are also involved in the development of diseases such as Alzheimer’s disease, epilepsy and depression. In order to understand the function of different types of iGluRs, selective agonists are invaluable as pharmacological tool compounds. Here, we report binding affinities of two bicyclic, conformationally restricted analogues of glutamate (CIP-AS and LM-12b) at AMPA (GluA2 and GluA3) and kainate receptor subunits (GluK1-3 and GluK5). Both CIP-AS and LM-12b were found to be GluK3-preferring agonists, with Ki of 6 and 22 nM, respectively, at recombinant GluK3 receptors. The detailed binding mode of CIP-AS and LM-12b in the ligand-binding domains of the AMPA receptor subunit GluA2 (GluA2-LBD) and the kainate receptor subunits GluK1 (GluK1-LBD) and GluK3 (GluK3-LBD) was investigated by X-ray crystallography. CIP-AS stabilized all three receptor constructs in conformations similar to those with kainate. Remarkably, whereas LM-12b bound in a similar manner to CIP-AS in GluA2-LBD and GluK3-LBD, it introduced full closure of the ligand-binding domain in GluK1-LBD and formation of a D1-D2 interlobe hydrogen bond between Glu441 and Ser721, as also observed with glutamate. As the binding affinity of LM-12b at GluK1 is ~8-fold better than for CIP-AS (Ki of 85 and 656 nM, respectively), it shows that small changes in agonist structure can lead to prominent differences in structure and function.
Original languageEnglish
JournalA C S Chemical Neuroscience
Issue number9
Pages (from-to)2056-2064
Number of pages9
Publication statusPublished - 2017

ID: 181004672