4ymb | pdb_00004ymb

Structure of the ligand-binding domain of GluK1 in complex with the antagonist CNG10111

spinqualitylabelsall models 4ymb, resolution 1.93Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ymb is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 4E7, ACT, CL, EDO, PEG Related: 4e0x Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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. Publication Abstract from PubMed Herein we describe the first structure-activity relationship study of the broad-range iGluR antagonist (2S,3R)-3-(3-carboxyphenyl)pyrrolidine-2-carboxylic acid (1) by exploring the pharmacological effect of substituents in the 4, 4', or 5' positions and the bioisosteric substitution of the distal carboxylic acid for a phosphonic acid moiety. Of particular interest is a hydroxyl group in the 4' position 2a which induced a preference in binding affinity for homomeric GluK3 over GluK1 (Ki = 0.87 and 4.8 muM, respectively). Two X-ray structures of ligand binding domains were obtained: 2e in GluA2-LBD and 2f in GluK1-LBD, both at 1.9 A resolution. Compound 2e induces a D1-D2 domain opening in GluA2-LBD of 17.3-18.8 degrees and 2f a domain opening in GluK1-LBD of 17.0-17.5 degrees relative to the structures with glutamate. The pyrrolidine-2-carboxylate moiety of 2e and 2f shows a similar binding mode as kainate. The 3-carboxyphenyl ring of 2e and 2f forms contacts comparable to those of the distal carboxylate in kainate. Structure-Activity Relationship Study of Ionotropic Glutamate Receptor Antagonist (2S,3R)-3-(3-Carboxyphenyl)pyrrolidine-2-carboxylic Acid.,Krogsgaard-Larsen N, Storgaard M, Moller C, Demmer CS, Hansen J, Han L, Monrad RN, Nielsen B, Tapken D, Pickering DS, Kastrup JS, Frydenvang K, Bunch L J Med Chem. 2015 Jul 22. PMID:26200741 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ionotropic Glutamate Receptors

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