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PDBsum entry 2v3u
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References listed in PDB file
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Key reference
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Title
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Ionotropic glutamate-Like receptor delta2 binds d-Serine and glycine.
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Authors
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P.Naur,
K.B.Hansen,
A.S.Kristensen,
S.M.Dravid,
D.S.Pickering,
L.Olsen,
B.Vestergaard,
J.Egebjerg,
M.Gajhede,
S.F.Traynelis,
J.S.Kastrup.
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Ref.
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Proc Natl Acad Sci U S A, 2007,
104,
14116-14121.
[DOI no: ]
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PubMed id
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Abstract
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The orphan glutamate-like receptor GluRdelta2 is predominantly expressed in
Purkinje cells of the central nervous system. The classification of GluRdelta2
to the ionotropic glutamate receptor family is based on sequence similarities,
because GluRdelta2 does not form functional homomeric glutamate-gated ion
channels in transfected cells. Studies in GluRdelta2(-/-) knockout mice as well
as in mice with naturally occurring mutations in the GluRdelta2 gene have
demonstrated an essential role of GluRdelta2 in cerebellar long-term depression,
motor learning, motor coordination, and synaptogenesis. However, the lack of a
known agonist has hampered investigations on the function of GluRdelta2. In this
study, the ligand-binding core of GluRdelta2 (GluRdelta2-S1S2) was found to bind
neutral amino acids such as D-serine and glycine, as demonstrated by isothermal
titration calorimetry. Direct evidence for binding of D-serine and structural
rearrangements in the binding cleft of GluRdelta2-S1S2 is provided by x-ray
structures of GluRdelta2-S1S2 in its apo form and in complex with D-serine.
Functionally, D-serine and glycine were shown to inactivate spontaneous
ion-channel conductance in GluRdelta2 containing the lurcher mutation (EC(50)
values, 182 and 507 microM, respectively). These data demonstrate that the
GluRdelta2 ligand-binding core is capable of binding ligands and that cleft
closure of the ligand-binding core can induce conformational changes that alter
ion permeation.
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Figure 1.
Fig. 1. The structure of the ligand-binding core of GluR
 2.
(A) Domain organization of the GluR 2 receptor subunit. The
architecture is similar to other glutamate receptors (AMPA,
kainate, and NMDA receptors), with an extracellular N terminus,
three transmembrane segments (M1, M2, and M3), a reentrant
membrane loop (P), and an intracellular C terminus. The
extracellular regions harbor the N-terminal domain (NTD) and the
ligand-binding core (D1 and D2). The red dot shows the
approximate position of the lurcher mutation (A654T). The
boundaries of the GluR 2–S1S2 construct are
indicated by scissors, and the dotted line represents the
Gly–Thr linker. (B) Representation of the twofold symmetric
dimer of GluR 2–S1S2 apo (in
yellow). The structure of GluR 2–S1S2 in complex
with D-serine has been superimposed onto GluR 2–S1S2
apo and is shown in red. D-serine is displayed as green spheres.
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Figure 3.
Fig. 3. The structure of the ligand-binding core of GluR
2
in complex with D-serine. (A) The D-serine-binding site of GluR
2–S1S2. The F[o] –
F[c] electron-density map of D-serine before introduction of
this molecule in the refinements is shown. D-serine and
potential hydrogen-bonding residues of GluR 2 are represented as
sticks, and dashed lines indicate hydrogen bonds. (B) Contour of
the ligand-binding cavity of GluR 2–S1S2 in complex
with D-serine (shown in gray). D-serine and GluR 2
residues within 3.5 Å are represented as sticks. No water
molecules were located within the hydrogen-bonding distance of
D-serine.
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