5m2v

Structure of GluK1 ligand-binding domain (S1S2) in complex with (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid at 3.18 A resolution

spinqualitylabelsall models 5m2v, resolution 3.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5m2v is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.18Å Ligands: 7E5, CL, SO4 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 Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 muM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 +/- 2 muM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14 degrees was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor. Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid.,Krogsgaard-Larsen N, Delgar CG, Koch K, Brown PM, Moller C, Han L, Huynh TH, Hansen SW, Nielsen B, Bowie D, Pickering DS, Kastrup JS, Frydenvang K, Bunch L J Med Chem. 2017 Jan 12;60(1):441-457. doi: 10.1021/acs.jmedchem.6b01516. Epub, 2016 Dec 22. PMID:28005385 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glutamate receptor 3D structures

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