Crystal structure of the gluk1 ligand-binding domain (s1s2) in complex with the antagonist (s)-2-amino-3-(2-(2-carboxyethyl)-5-chloro-4- nitrophenyl)propionic acid at 2.0 a resolution
Structure:
Glutamate receptor, ionotropic kainate 1. Chain: a, b. Fragment: gluk1 ligand binding domain (gluk1-s1s2). Synonym: glutamate receptor 5, glur-5, glur5. Engineered: yes. Other_details: the protein crystallized is the extracellular ligand binding domain of gluk1. Transmembrane regions were genetically removed and replaced with a gly-thr linker.
Continued efforts into the discovery of ligands that target ionotropic glutamate
receptors (iGluRs) are important for studies of the physiological roles of the
various iGluR subtypes as well as for the search for drugs that can be used in
the treatment of diseases of the central nervous system. A new series of
phenylalanine derivatives that target iGluRs was reported to bind AMPA
receptors. Herein we report our studies of these compounds at the kainate
receptors GluK1-3. Several compounds bind with micromolar affinity at GluK1 and
GluK3, but do not bind GluK2. The crystal structure of the most potent compound
in the ligand binding domain of GluK1 revealed different modes of binding to
GluK1 and GluA2, due primarily to residues Ser741 (GluK1) and Met729 (GluA2).
The compound was shown to be slightly more potent at GluK1 than at AMPA
receptors and to induce a domain closure similar to that observed in GluK1
structures with partial agonists.
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