Structural highlights
Function
[GRIK1_RAT] Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. May be involved in the transmission of light information from the retina to the hypothalamus.[1]
Publication Abstract from PubMed
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.
Structural and pharmacological characterization of phenylalanine-based AMPA receptor antagonists at kainate receptors.,Venskutonyte R, Frydenvang K, Valades EA, Szymanska E, Johansen TN, Kastrup JS, Pickering DS ChemMedChem. 2012 Oct;7(10):1793-8. doi: 10.1002/cmdc.201100599. Epub 2012 Mar 7. PMID:22407805[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mayer ML, Ghosal A, Dolman NP, Jane DE. Crystal structures of the kainate receptor GluR5 ligand binding core dimer with novel GluR5-selective antagonists. J Neurosci. 2006 Mar 15;26(11):2852-61. PMID:16540562 doi:26/11/2852
- ↑ Venskutonyte R, Frydenvang K, Valades EA, Szymanska E, Johansen TN, Kastrup JS, Pickering DS. Structural and pharmacological characterization of phenylalanine-based AMPA receptor antagonists at kainate receptors. ChemMedChem. 2012 Oct;7(10):1793-8. doi: 10.1002/cmdc.201100599. Epub 2012 Mar 7. PMID:22407805 doi:http://dx.doi.org/10.1002/cmdc.201100599
