1. Department of Biochemistry and Molecular Biophysics and
2. Howard Hughes Medical Institute, Columbia University, 650 West 168th Street, New York, New York 10032, USA
3. †Present addresses: Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA (H.F., S.K.S., E.G.); The Structural Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, USA (R.M.)

Correspondence to: Eric Gouaux^1,2,3 Correspondence and requests for materials should be addressed to E.G. (Email: jeg52@columbia.edu). The coordinates and structure factors for NR1-NR2A S1S2 and NR2A S1S2-glutamate have been deposited in the Protein Data Bank with accession codes 2A5T and 2A5S, respectively.

Abstract

Excitatory neurotransmission mediated by NMDA (N-methyl-d-aspartate) receptors is fundamental to the physiology of the mammalian central nervous system. These receptors are heteromeric ion channels that for activation require binding of glycine and glutamate to the NR1 and NR2 subunits, respectively. NMDA receptor function is characterized by slow channel opening and deactivation, and the resulting influx of cations initiates signal transduction cascades that are crucial to higher functions including learning and memory. Here we report crystal structures of the ligand-binding core of NR2A with glutamate and that of the NR1–NR2A heterodimer with glutamate and glycine. The NR2A–glutamate complex defines the determinants of glutamate and NMDA recognition, and the NR1–NR2A heterodimer suggests a mechanism for ligand-induced ion channel opening. Analysis of the heterodimer interface, together with biochemical and electrophysiological experiments, confirms that the NR1–NR2A heterodimer is the functional unit in tetrameric NMDA receptors and that tyrosine 535 of NR1, located in the subunit interface, modulates the rate of ion channel deactivation.

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