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PDBsum entry 4nf4
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Transport protein, receptor
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PDB id
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4nf4
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References listed in PDB file
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Key reference
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Title
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Structural insights into competitive antagonism in nmda receptors.
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Authors
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A.Jespersen,
N.Tajima,
G.Fernandez-Cuervo,
E.C.Garnier-Amblard,
H.Furukawa.
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Ref.
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Neuron, 2014,
81,
366-378.
[DOI no: ]
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PubMed id
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Abstract
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There has been a great level of enthusiasm to downregulate overactive
N-methyl-D-aspartate (NMDA) receptors to protect neurons from excitotoxicity.
NMDA receptors play pivotal roles in basic brain development and functions as
well as in neurological disorders and diseases. However, mechanistic
understanding of antagonism in NMDA receptors is limited due to complete lack of
antagonist-bound structures for the L-glutamate-binding GluN2 subunits. Here, we
report the crystal structures of GluN1/GluN2A NMDA receptor ligand-binding
domain (LBD) heterodimers in complex with GluN1- and GluN2-targeting
antagonists. The crystal structures reveal that the antagonists,
D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) and
1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA), have
discrete binding modes and mechanisms for opening of the bilobed architecture of
GluN2A LBD compared to the agonist-bound form. The current study shows distinct
ways by which the conformations of NMDA receptor LBDs may be controlled and
coupled to receptor inhibition and provides possible strategies to develop
therapeutic compounds with higher subtype-specificity.
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