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PDBsum entry 3dln
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Signaling protein
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PDB id
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3dln
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References listed in PDB file
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Key reference
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Title
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Structure of the s1s2 glutamate binding domain of glur3.
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Authors
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A.H.Ahmed,
Q.Wang,
H.Sondermann,
R.E.Oswald.
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Ref.
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Proteins, 2008,
75,
628-637.
[DOI no: ]
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PubMed id
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Abstract
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Glutamate receptors are the most prevalent excitatory neurotransmitter receptors
in the vertebrate central nervous system. Determining the structural differences
between the binding sites of different subtypes is crucial to our understanding
of neuronal circuits and to the development of subtype specific drugs. The
structures of the binding domain (S1S2) of the GluR3 (flip) AMPA receptor
subunit bound to glutamate and AMPA and the GluR2 (flop) subunit bound to
glutamate were determined by X-ray crystallography to 1.9, 2.1, and 1.55 A,
respectively. Overall, the structure of GluR3 (flip) S1S2 is very similar to
GluR2 (flop) S1S2 (backbone RMSD of 0.30 +/- 0.05 for glutamate-bound and 0.26
+/- 0.01 for AMPA-bound). The differences in the flip and flop isoforms are
subtle and largely arise from one hydrogen bond across the dimer interface and
associated water molecules. Comparison of the binding affinity for various
agonists and partial agonists suggest that the S1S2 domains of GluR2 and GluR3
show only small differences in affinity, unlike what is found for the intact
receptors (with the exception of one ligand, Cl-HIBO, which has a 10-fold
difference in affinity for GluR2 vs. GluR3). Proteins 2009. (c) 2008 Wiley-Liss,
Inc.
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Figure 3.
Figure 3. (A) The dimeric structure of GluR3 bound to
glutamate. The helices are labeled as in Armstrong et al.[6]
Residues participating in contacts across the dimer interface
are labeled. P632 (yellow) flanks the artificial linker region
of the construct and is the point that connects to the linkers
to the ion channel. The four residues that differ in flip and
flop are shown in shades of red. (B) The dimer interface at the
S754 (flip)/N754 (flop) interaction with S729. Both can form
hydrogen bonds, but the structure of the water surrounding the
hydrogen bond differs.
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Figure 4.
Figure 4. (A) Binding of [^3H]AMPA to the S1S2 domains of
GluR2[o] and GluR3[i]. The K[D] of binding differed by less than
twofold: 19 ± 2 nM for GluR2 and 43 ± 5 nM for
GluR3. Armstrong and Gouaux[5] reported a K[D] of 24.8 ±
1.8 nM for [^3H]AMPA binding to GluR2. (B) Structures of the
ligands used in the binding studies, (C) The inhibition of
[^3H]AMPA binding by agonists, partial agonists, and antagonist
to the S1S2 domains of GluR2[o] and GluR3[i]. Except for
willardiine, the IC[50] values were within twofold for the two
subtypes: (ligand, GluR2 IC[50]/GluR3 IC[50]; IC[50] expressed
in  M)
fluorowillardiine, 0.0040 ± 0009/0.0062 ± 0.0014;
iodowillardiine, 0.46 ± 0.05/0.79 ± 0.14; Cl-HIBO,
5.0 ± 0.3/55 ± 4; willardiine, 3.1 ±
0.2/0.99 ± 0.18; UBP277, 135 ± 12/69 ± 10.
In all cases, GluR2[o] is shown with filled symbols, and
GluR3[i] is shown with open symbols.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2008,
75,
628-637)
copyright 2008.
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