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PDBsum entry 3gbb
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Membrane protein
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PDB id
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3gbb
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References listed in PDB file
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Key reference
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Title
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Full domain closure of the ligand-Binding core of the ionotropic glutamate receptor iglur5 induced by the high-Affinity agonist dysiherbaine and the functional antagonist msviii-19.
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Authors
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K.Frydenvang,
L.L.Lash,
P.Naur,
P.A.Postila,
D.S.Pickering,
C.M.Smith,
M.Gajhede,
M.Sasaki,
R.Sakai,
O.T.Pentikäinen,
G.T.Swanson,
J.S.Kastrup.
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Ref.
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J Biol Chem, 2009,
284,
14219-14229.
[DOI no: ]
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PubMed id
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Abstract
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The prevailing structural model for ligand activation of ionotropic glutamate
receptors posits that agonist efficacy arises from the stability and magnitude
of induced domain closure in the ligand-binding core structure. Here we describe
an exception to the correlation between ligand efficacy and domain closure. A
weakly efficacious partial agonist of very low potency for homomeric iGluR5
kainate receptors, 8,9-dideoxy-neodysiherbaine (MSVIII-19), induced a fully
closed iGluR5 ligand-binding core. The degree of relative domain closure, ~30
degrees , was similar to that we resolved with the structurally related
high-affinity agonist dysiherbaine (DH), and to that of L-glutamate. The
pharmacological activity of MSVIII-19 was confirmed in patch-clamp recordings
from transfected HEK293 cells, where MSVIII-19 predominantly inhibits iGluR5-2a,
with little activation apparent at a high concentration (1 mM) of MSVIII-19
(<1% of mean glutamate-evoked currents). To determine the efficacy of the
ligand quantitatively, we constructed concentration-response relationships for
MSVIII-19 following potentiation of steady-state currents with concanavalin A
(EC50 3.6 muM) and on the non-desensitizing receptor mutant
iGluR5-2b(Y506C/L768C) (EC50 8.1 muM). MSVIII-19 exhibited a maximum of 16% of
full agonist efficacy as measured in parallel recordings with glutamate.
Molecular dynamics simulations and electrophysiological recordings confirm that
the specificity of MSVIII-19 for iGluR5 is partly attributable to inter-domain
hydrogen bonds residues Glu441 and Ser721 in the iGluR5-S1S2 structure. The
weaker interactions of MSVIII-19 with iGluR5 compared to DH, together with
altered stability of the inter-domain interaction, may be responsible for the
apparent uncoupling of domain closure and channel opening in this kainate
receptor subunit.
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Figure 1.
Chemical structures of dysiherbaine and MSVIII-19. The two
compounds differ in positions C8 (NH-Me substituent in DH versus
H in MSVIII-19) and C9 (OH versus H).
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Figure 3.
MSVIII-19 induces full domain closure in the ligand-binding
core of iGluR5. A, superimposition of the MSVIII-19 (cyan), DH
(yellow), and l-glutamate (Protein Data Bank code 1YCJ, molecule
A; salmon) complexes with iGluR5-S1S2 on D1 residues. B,
superimposition of the MSVIII-19 (cyan) and UBP302 (Protein Data
Bank code 2F35, molecule A; blue) complexes with iGluR5-S1S2 on
D1 residues. The high degree of domain closure introduced by
MSVIII-19 compared with UBP302 is evident from the change of the
D2 domain position.
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2009,
284,
14219-14229)
copyright 2009.
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Secondary reference #1
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Title
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Crystal structure of the kainate receptor glur5 ligand-Binding core in complex with (s)-Glutamate.
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Authors
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P.Naur,
B.Vestergaard,
L.K.Skov,
J.Egebjerg,
M.Gajhede,
J.S.Kastrup.
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Ref.
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FEBS Lett, 2005,
579,
1154-1160.
[DOI no: ]
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PubMed id
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Figure 1.
Fig. 1. Ligand-binding cores of the three classes of
iGluRs. Cartoon representations of the overall structures of the
AMPA receptor GluR2-S1S2J (MolB, pdb code 1FTJ; left figure),
the kainate receptor GluR5-S1S2 (MolB; middle figure) and the
NMDA receptor NR1-S1S2 (MolA, pdb code 1PB7; right figure).
Domain D1 (primarily composed of S1 residues) is colored cyan
and D2 (primarily composed of S2 residues) is colored brown.
GluR2-S1S2J and GluR5-S1S2 were crystallized in the presence of
(S)-glutamate, whereas NR1 was crystallized in complex with
(S)-glycine. The ligands are shown in ball-and-stick
representation.
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Figure 2.
Fig. 2. Comparison of the structures of GluR5-S1S2 and
GluR2-S1S2J. (A) Structural alignment of GluR5-S1S2 and
GluR2-S1S2J. Boxes correspond to structurally conserved regions.
The Gly-Thr linker is shaded grey. (B) Superimposition of the D1
Cα-atoms of the structures of GluR5-S1S2 and GluR2-S1S2J. A
Cα-trace of the two structures is shown in stereo, with
GluR5-S1S2 coloured in green and GluR2-S1S2J in magenta. Every
10th residue of the GluR5-S1S2 structure is labeled.
(S)-glutamate is shown in ball-and-stick.
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The above figures are
reproduced from the cited reference
with permission from the Federation of European Biochemical Societies
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