Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 288, Issue 31, Pages 22555-22564Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M113.482356
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Funding
- Houston Area Molecular Biophysics Training Program National Institutes of Health [2T32GM008280]
- American Heart Association
- National Institutes of Health [GM094246]
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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.
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