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PDBsum entry 2ipv
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Membrane protein
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PDB id
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2ipv
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References listed in PDB file
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Key reference
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Title
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Subunit arrangement and function in nmda receptors.
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Authors
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H.Furukawa,
S.K.Singh,
R.Mancusso,
E.Gouaux.
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Ref.
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Nature, 2005,
438,
185-192.
[DOI no: ]
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PubMed id
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Abstract
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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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Figure 2.
Figure 2: Structure of NR1-NR2A S1S2. a, Side view of the
NR1-NR2A S1S2 heterodimer in complex with glycine and glutamate.
NR1 and NR2A are coloured green and blue, respectively. Glycine,
glutamate and the C  atom
of the glycine residue in the Gly-Thr dipeptide linker are shown
as spheres. The arrow indicates the pseudo two-fold axis between
the protomers. b, View of the structure from the 'top'. The
interface between NR1 and NR2A is sliced into three sections
denoted sites I-III. c-e, Magnified view of the interactions at
sites I, II and III. Dashed lines indicate hydrogen bonds or
salt bridges. The interacting residues from NR1 and NR2A are
coloured white and orange, respectively. f, g, Structural
comparison between the NR1-NR2A (green-blue) S1S2 heterodimer
and the glutamate-bound GluR2 S1S2 (pink) homodimer (PDB code
1FTJ). Superimposed structures are viewed from the side and
'top' of the molecules in f and g, respectively. Superposition
was carried out on 256 residues from domain 1 with the program
LSQKAB^50. The C atoms
of the glycine residues in the Gly-Thr dipeptide linkers are
shown as spheres.
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Figure 5.
Figure 5: Superposition of NR1-NR2A S1S2 and the GluR2
S1S2-aniracetam complex. a, Overlay of the GluR2 S1S2 dimer
bound to glutamate and aniracetam (Ani, pink) onto the NR1-NR2A
S1S2 dimer (green and blue) viewed from the same angle as in
Fig. 1b. b, Magnification of the NR1 Y535 site and the
aniracetam-binding site viewed from the same angle as in a. Two
water molecules, W1 and W2 (cyan spheres), participate in
stabilizing the NR1-NR2A interaction. c, Side view of the NR1
Y535 site. Note that the position of the aniracetam molecule
(pink) overlaps with that of the aromatic side chain of NR1 Y535.
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The above figures are
reprinted
by permission from Macmillan Publishers Ltd:
Nature
(2005,
438,
185-192)
copyright 2005.
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