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PDBsum entry 5jty
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Transport protein, receptor
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PDB id
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5jty
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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 basis for negative allosteric modulation of glun2a-Containing nmda receptors.
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Authors
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F.Yi,
T.C.Mou,
K.N.Dorsett,
R.A.Volkmann,
F.S.Menniti,
S.R.Sprang,
K.B.Hansen.
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Ref.
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Neuron, 2016,
91,
1316-1329.
[DOI no: ]
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PubMed id
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Abstract
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NMDA receptors mediate excitatory synaptic transmission and regulate synaptic
plasticity in the central nervous system, but their dysregulation is also
implicated in numerous brain disorders. Here, we describe GluN2A-selective
negative allosteric modulators (NAMs) that inhibit NMDA receptors by stabilizing
the apo state of the GluN1 ligand-binding domain (LBD), which is incapable of
triggering channel gating. We describe structural determinants of NAM binding in
crystal structures of the GluN1/2A LBD heterodimer, and analyses of NAM-bound
LBD structures corresponding to active and inhibited receptor states reveal a
molecular switch in the modulatory binding site that mediate the allosteric
inhibition. NAM binding causes displacement of a valine in GluN2A and the
resulting steric effects can be mitigated by the transition from glycine bound
to apo state of the GluN1 LBD. This work provides mechanistic insight to
allosteric NMDA receptor inhibition, thereby facilitating the development of
novel classes NMDA receptor modulators as therapeutic agents.
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