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Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors.
Feng Yi1, Tung-Chung Mou2, Katherine N Dorsett1
1Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
Neuron
|September 13, 2016
Summary
Researchers developed GluN2A-selective negative allosteric modulators (NAMs) that inhibit NMDA receptors by stabilizing the apo state. This discovery offers new therapeutic strategies for brain disorders linked to NMDA receptor dysregulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- NMDA receptors are crucial for synaptic transmission and plasticity in the central nervous system.
- Dysregulation of NMDA receptors is linked to various brain disorders.
Purpose of the Study:
- To describe GluN2A-selective negative allosteric modulators (NAMs) that inhibit NMDA receptors.
- To elucidate the structural and mechanistic basis of this allosteric inhibition.
Main Methods:
- X-ray crystallography of the GluN1/2A ligand-binding domain (LBD) heterodimer.
- Analysis of NAM-bound LBD structures in different receptor states.
Main Results:
- Identified NAMs that stabilize the apo state of the GluN1 LBD, preventing channel gating.
- Determined structural determinants of NAM binding and a molecular switch mechanism.
- Observed that NAM binding displaces a valine in GluN2A, with steric effects modulated by the GluN1 LBD state.
Conclusions:
- Provided mechanistic insight into allosteric NMDA receptor inhibition.
- Facilitated the development of novel NMDA receptor modulators for therapeutic applications.
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