2CMO

The structure of a mixed glur2 ligand-binding core dimer in complex with (s)-glutamate and the antagonist (s)-ns1209

Summary for 2CMO

• Entry DOI: 10.2210/pdb2cmo/pdb
• Related: 1FTJ 1FTK 1FTL 1FTM 1FTO 1FW0 1GR2 1LB8 1LB9 1LBB 1LBC 1M5B 1M5C 1M5D 1M5E 1M5F 1MM6 1MM7 1MQD 1MQG 1MQH 1MQI 1MQJ 1MS7 1MXU 1MXV 1MXW 1MXX 1MXY 1MXZ 1MY0 1MY1 1MY2 1MY3 1MY4 1N0T 1NNK 1NNP 1P1N 1P1O 1P1Q 1P1U 1P1W 1SYH 1SYI 1WVJ 1XHY 2AIX 2AL4 2AL5 2ANJ
• Descriptor: GLUTAMATE RECEPTOR 2, SULFATE ION, 2-({[(3E)-5-{4-[(DIMETHYLAMINO)(DIHYDROXY)-LAMBDA~4~-SULFANYL]PHENYL}-8-METHYL-2-OXO-6,7,8,9-TETRAHYDRO-1H-PYRROLO[3,2-H]ISOQUINOLIN-3(2H)-YLIDENE]AMINO}OXY)-4-HYDROXYBUTANOIC ACID, ... (5 entities in total)
• Functional Keywords: membrane, receptor, palmitate, transport, postsynaptic membrane, glycoprotein, ionic channel, ion transport, transmembrane, alternative splicing, rna editing, lipoprotein, ion channel
• Biological source: RATTUS NORVEGICUS (RAT)
• Cellular location: Cell membrane; Multi-pass membrane protein: P19491
• Total number of polymer chains: 2
• Total formula weight: 59493.33

Authors

Kasper, C.,Pickering, D.S.,Mirza, O.,Olsen, L.,Kristensen, A.S.,Greenwood, J.R.,Liljefors, T.,Schousboe, A.,Watjen, F.,Gajhede, M.,Sigurskjold, B.W.,Kastrup, J.S. (deposition date: 2006-05-11, release date: 2006-06-06, Last modification date: 2023-12-13)

Primary citation

Kasper, C.,Pickering, D.S.,Mirza, O.,Olsen, L.,Kristensen, A.S.,Greenwood, J.R.,Liljefors, T.,Schousboe, A.,Watjen, F.,Gajhede, M.,Sigurskjold, B.W.,Kastrup, J.S.
The Structure of a Mixed Glur2 Ligand-Binding Core Dimer in Complex with (S)-Glutamate and the Antagonist (S)-Ns1209.
J.Mol.Biol., 357:1184-, 2006

PubMed Abstract: 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-pyrrolo[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.

PubMed: 16483599
DOI: 10.1016/J.JMB.2006.01.024

Experimental method

X-RAY DIFFRACTION (2.65 Å)