1 research outputs found
Structure and Affinity of Two Bicyclic Glutamate Analogues at AMPA and Kainate Receptors
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. 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 <i>K</i><sub>i</sub> 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 that for CIP-AS (<i>K</i><sub>i</sub> of 85
and 656 nM, respectively), it shows that small changes in agonist
structure can lead to prominent differences in structure and function