2wky is a 2 chain structure with sequence from Buffalo rat. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
[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]
Evolutionary Conservation
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Publication Abstract from PubMed
The design, synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta[d]isoxazo l-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propion ic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)-glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.
The Glutamate Receptor GluR5 Agonist (S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propion ic Acid and the 8-Methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization (dagger) dagger PDB ID: 2WKY .,Clausen RP, Naur P, Kristensen AS, Greenwood JR, Strange M, Brauner-Osborne H, Jensen AA, Nielsen AS, Geneser U, Ringgaard LM, Nielsen B, Pickering DS, Brehm L, Gajhede M, Krogsgaard-Larsen P, Kastrup JS J Med Chem. 2009 Jul 9. PMID:19588945[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑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
↑Clausen RP, Naur P, Kristensen AS, Greenwood JR, Strange M, Brauner-Osborne H, Jensen AA, Nielsen AS, Geneser U, Ringgaard LM, Nielsen B, Pickering DS, Brehm L, Gajhede M, Krogsgaard-Larsen P, Kastrup JS. The Glutamate Receptor GluR5 Agonist (S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propion ic Acid and the 8-Methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization (dagger) dagger PDB ID: 2WKY . J Med Chem. 2009 Jul 9. PMID:19588945 doi:10.1021/jm900565c
