Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core

Furukawa, H., Gouaux, E. (2003) Mechanisms of activation, inhibition and specificity: crystal structures of the NMDA receptor NR1 ligand-binding core. Embo J, 22 (12). pp. 2873-85. ISSN 0261-4189 (Print)0261-4189 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/12805203
DOI: 10.1093/emboj/cdg303

Abstract

Excitatory neurotransmission mediated by the N-methyl-D-aspartate subtype of ionotropic glutamate receptors is fundamental to the development and function of the mammalian central nervous system. NMDA receptors require both glycine and glutamate for activation with NR1 and NR2 forming glycine and glutamate sites, respectively. Mechanisms to describe agonist and antagonist binding, and activation and desensitization of NMDA receptors have been hampered by the lack of high-resolution structures. Here, we describe the cocrystal structures of the NR1 S1S2 ligand-binding core with the agonists glycine and D-serine (DS), the partial agonist D-cycloserine (DCS) and the antagonist 5,7-dichlorokynurenic acid (DCKA). The cleft of the S1S2 'clamshell' is open in the presence of the antagonist DCKA and closed in the glycine, DS and DCS complexes. In addition, the NR1 S1S2 structure reveals the fold and interactions of loop 1, a cysteine-rich region implicated in intersubunit allostery.

Item Type: Paper
Uncontrolled Keywords: Amino Acid Sequence Animals Binding Sites Crystallography X-Ray Disulfides chemistry metabolism Excitatory Amino Acid Agonists chemistry metabolism Excitatory Amino Acid Antagonists metabolism Glycine chemistry metabolism Kynurenic Acid analogs & derivatives metabolism Models Molecular Molecular Sequence Data Molecular Structure Protein Binding Protein Conformation Protein Subunits chemistry genetics metabolism Rats Receptors AMPA chemistry genetics metabolism Receptors N-Methyl-D-Aspartate chemistry genetics metabolism Sequence Alignment Serine chemistry metabolism
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > glutamate receptor
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Leigh Johnson
Date Deposited: 06 Mar 2012 19:13
Last Modified: 08 Sep 2017 16:31
PMCID: PMC162155
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Dataset ID:
URI: http://repository.cshl.edu/id/eprint/25170

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