Mechanism of partial agonist action at the NR1 subunit of NMDA receptors

Inanobe, A., Furukawa, H., Gouaux, E. (2005) Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. Neuron, 47 (1). pp. 71-84. ISSN 0896-6273 (Print)0896-6273 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/15996549
DOI: 10.1016/j.neuron.2005.05.022

Abstract

Partial agonists produce submaximal activation of ligand-gated ion channels. To address the question of partial agonist action at the NR1 subunit of the NMDA receptor, we performed crystallographic and electrophysiological studies with 1-aminocyclopropane-1-carboxylic acid (ACPC), 1-aminocyclobutane-1-carboxylic acid (ACBC), and 1-aminocyclopentane-1-carboxylic acid (cycloleucine), three compounds with incrementally larger carbocyclic rings. Whereas ACPC and ACBC partially activate the NMDA receptor by 80% and 42%, respectively, their cocrystal structures of the NR1 ligand binding core show the same degree of domain closure as found in the complex with glycine, a full agonist, illustrating that the NR1 subunit provides a new paradigm for partial agonist action that is distinct from that of the evolutionarily related GluR2, AMPA-sensitive receptor. Cycloleucine behaves as an antagonist and stabilizes an open-cleft conformation. The NR1-cycloleucine complex forms a dimer that is similar to the GluR2 dimer, thereby suggesting a conserved mode of subunit-subunit interaction in AMPA and NMDA receptors.

Item Type: Paper
Uncontrolled Keywords: Amino Acids Cyclic pharmacology Animals Binding Competitive drug effects Crystallography X-Ray Cycloleucine pharmacology Electrophysiology Excitatory Amino Acid Agonists pharmacology Female Kinetics Ligands Models Molecular Mutation Oocytes metabolism Patch-Clamp Techniques Protein Conformation Rats Receptors AMPA metabolism Receptors Glycine drug effects metabolism Receptors N-Methyl-D-Aspartate agonists antagonists & inhibitors genetics Xenopus
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
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
Investigative techniques and equipment > X-Ray Diffraction
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > ion channel
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Furukawa lab
Depositing User: Leigh Johnson
Date Deposited: 06 Mar 2012 19:26
Last Modified: 08 Sep 2017 16:29
Related URLs:
Dataset ID:
URI: http://repository.cshl.edu/id/eprint/25167

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