2cmo

File:2cmo.gif

spinqualitylabelsall models 2cmo, resolution 2.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

THE STRUCTURE OF A MIXED GLUR2 LIGAND-BINDING CORE DIMER IN COMPLEX WITH (S)-GLUTAMATE AND THE ANTAGONIST (S)-NS1209

OverviewOverview

Ionotropic glutamate receptors (iGluRs) mediate fast synaptic transmission, between cells of the central nervous system and are involved in various, aspects of normal brain function. iGluRs are implicated in several brain, disorders, e.g. in the high-frequency discharge of impulses during an, epileptic seizure. (RS)-NS1209 functions as a competitive antagonist at, 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptors, and shows, robust preclinical anticonvulsant and neuroprotective effects. This study, explores 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionate receptor, binding and selectivity of this novel class of antagonists. We present, here the first X-ray structure of a mixed GluR2 ligand-binding core dimer, with the high-affinity antagonist, (S)-8-methyl-5-(4-(N,N-dimethylsulfamoyl)phenyl)-6,7,8,9,-tetrahydro-1H-py, rrolo[3,2-h]-isoquinoline-2,3-dione-3-O-(4-hydroxybutyrate-2-yl)oxime, [(S)-NS1209] in one protomer and the endogenous ligand (S)-glutamate in, the other. (S)-NS1209 stabilises an even more open conformation of the D1, and D2 domains of the ligand-binding core than that of the apo structure, due to steric hindrance. This is the first time ligand-induced, hyperextension of the binding domains has been observed. (S)-NS1209 adopts, a novel binding mode, including hydrogen bonding to Tyr450 and Gly451 of, D1. Parts of (S)-NS1209 occupy new areas of the GluR2 ligand-binding, cleft, and bind near residues that are not conserved among receptor, subtypes. The affinities of (RS)-NS1209 at the GluR2 ligand-binding core, as well as at GluR1-6 and mutated GluR1 and GluR3 receptors have been, measured. Two distinct binding affinities were observed at the GluR3 and, GluR4 receptors. In a functional in vitro assay, no difference in potency, was observed between GluR2(Q)(o) and GluR3(o) receptors. The, thermodynamics of binding of the antagonists (S)-NS1209, DNQX and (S)-ATPO, to the GluR2 ligand-binding core have been determined by displacement, isothermal titration calorimetry. The displacement of (S)-glutamate by all, antagonists was shown to be driven by enthalpy.

About this StructureAbout this Structure

2CMO is a Single protein structure of sequence from Rattus norvegicus with SO4, GLU and M1L as ligands. Structure known Active Site: AC1. Full crystallographic information is available from OCA.

ReferenceReference

The structure of a mixed GluR2 ligand-binding core dimer in complex with (S)-glutamate and the antagonist (S)-NS1209., Kasper C, Pickering DS, Mirza O, Olsen L, Kristensen AS, Greenwood JR, Liljefors T, Schousboe A, Watjen F, Gajhede M, Sigurskjold BW, Kastrup JS, J Mol Biol. 2006 Apr 7;357(4):1184-201. Epub 2006 Jan 31. PMID:16483599

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