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J Biol Chem. 2013 Aug 2;288(31):22555-64. doi: 10.1074/jbc.M113.482356. Epub 2013 Jun 21.

Amino-terminal domain tetramer organization and structural effects of zinc binding in the N-methyl-D-aspartate (NMDA) receptor.

Author information

1
Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, Texas 77030, USA.

Abstract

N-Methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian central nervous system. An important feature of these receptors is their capacity for allosteric regulation by small molecules, such as zinc, which bind to their amino-terminal domain (ATD). Zinc inhibition through high affinity binding to the ATD has been examined through functional studies; however, there is no direct measurement of associated conformational changes. We used luminescence resonance energy transfer to show that the ATDs undergo a cleft closure-like conformational change upon binding zinc, but no changes are observed in intersubunit distances. Furthermore, we find that the ATDs are more closely packed than the related AMPA receptors. These results suggest that the stability of the upper lobe contacts between ATDs allow for the efficient propagation of the cleft closure conformational change toward the ligand-binding domain and transmembrane segments, ultimately inhibiting the channel.

KEYWORDS:

Allosteric Regulation; Amino-terminal Domain; Fluorescence Resonance Energy Transfer (FRET); Glutamate Receptors Ionotropic (AMPA, NMDA); Ion Channels; LRET; Zinc

PMID:
23792960
PMCID:
PMC3829342
DOI:
10.1074/jbc.M113.482356
[Indexed for MEDLINE]
Free PMC Article

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