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PDBsum entry 4nwd
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Membrane protein/agonist
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PDB id
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4nwd
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References listed in PDB file
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Key reference
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Title
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Molecular recognition of two 2,4-Syn-Functionalized (s)-Glutamate analogues by the kainate receptor gluk3 ligand binding domain.
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Authors
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R.Venskutonytė,
A.P.Larsen,
K.Frydenvang,
M.Gajhede,
E.Sagot,
Z.Assaf,
T.Gefflaut,
D.S.Pickering,
L.Bunch,
J.S.Kastrup.
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Ref.
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Chemmedchem, 2014,
9,
2254-2259.
[DOI no: ]
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PubMed id
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Abstract
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The kainate receptors are the least studied subfamily of ionotropic glutamate
receptors. These receptors are thought to have a neuromodulatory role and have
been associated with a variety of disorders in the central nervous system. This
makes kainate receptors interesting potential drug targets. Today, structures of
the ligand binding domain (LBD) of the kainate receptor GluK3 are only known in
complex with the endogenous agonist glutamate, the natural product kainate, and
two synthetic agonists. Herein we report structures of GluK3 LBD in complex with
two 2,4-syn-functionalized (S)-glutamate analogues to investigate their
structural potential as chemical scaffolds. Similar binding affinities at GluK3
were determined for the 2-(methylcarbamoyl)ethyl analogue (Ki =4.0 μM) and
the 2-(methoxycarbonyl)ethyl analogue (Ki =1.7 μM), in agreement with the
similar positioning of the compounds within the binding pocket. As the binding
affinity is similar to that of glutamate, this type of Cγ substituent could be
used as a scaffold for introduction of even larger substituents reaching into
unexplored binding site regions to achieve subtype selectivity.
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Secondary reference #1
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Title
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Binding site and interlobe interactions of the ionotropic glutamate receptor gluk3 ligand binding domain revealed by high resolution crystal structure in complex with (s)-Glutamate.
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Authors
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R.Venskutonytė,
K.Frydenvang,
M.Gajhede,
L.Bunch,
D.S.Pickering,
J.S.Kastrup.
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Ref.
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J Struct Biol, 2011,
176,
307-314.
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PubMed id
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