Channelpedia

PubMed 25404733


Referenced in: none

Automatically associated channels: Slo1



Title: Structural dynamics of the glycine-binding domain of the N-methyl-D-aspartate receptor.

Authors: Drew M Dolino, David Cooper, Swarna Ramaswamy, Henriette Jaurich, Christy F Landes, Vasanthi Jayaraman

Journal, date & volume: J. Biol. Chem., 2015 Jan 9 , 290, 797-804

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/25404733


Abstract
N-Methyl-D-aspartate receptors mediate the slow component of excitatory neurotransmission in the central nervous system. These receptors are obligate heteromers containing glycine- and glutamate-binding subunits. The ligands bind to a bilobed agonist-binding domain of the receptor. Previous x-ray structures of the glycine-binding domain of NMDA receptors showed no significant changes between the partial and full agonist-bound structures. Here we have used single molecule fluorescence resonance energy transfer (smFRET) to investigate the cleft closure conformational states that the glycine-binding domain of the receptor adopts in the presence of the antagonist 5,7-dichlorokynurenic acid (DCKA), the partial agonists 1-amino-1-cyclobutanecarboxylic acid (ACBC) and L-alanine, and full agonists glycine and D-serine. For these studies, we have incorporated the unnatural amino acid p-acetyl-L-phenylalanine for specific labeling of the protein with hydrazide derivatives of fluorophores. The single molecule fluorescence resonance energy transfer data show that the agonist-binding domain can adopt a wide range of cleft closure states with significant overlap in the states occupied by ligands of varying efficacy. The difference lies in the fraction of the protein in a more closed-cleft form, with full agonists having a larger fraction in the closed-cleft form, suggesting that the ability of ligands to select for these states could dictate the extent of activation.