Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors

Authors

Feng Yi, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
Tung-Chung Mou, Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT 59812, USA; Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA.
Katherine N. Dorsett, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA.
Robert A. Volkmann, BioPharmaWorks, LLC, Groton, CT 06340, USA.
Frank S. Menniti, MindImmune Therapeutics, Inc., and George & Anne Ryan Institute for Neuroscience, Kingston, RI 02881, USA.
Stephen R. Sprang, Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT 59812, USA; Division of Biological Sciences, University of Montana, Missoula, MT 59812, USA.Follow
Kasper B. Hansen, Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT 59812, USA; Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT 59812, USA. Electronic address: kasper.hansen@mso.umt.edu.

Document Type

Article

Publication Title

Neuron

Publication Date

9-21-2016

Volume

91

Issue

6

Disciplines

Biology | Life Sciences

Abstract

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.

DOI

10.1016/j.neuron.2016.08.014

Rights

© 2016 Elsevier Inc.

Recommended Citation

Yi, Feng; Mou, Tung-Chung; Dorsett, Katherine N.; Volkmann, Robert A.; Menniti, Frank S.; Sprang, Stephen R.; and Hansen, Kasper B., "Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors" (2016). Biological Sciences Faculty Publications. 482.
https://scholarworks.umt.edu/biosci_pubs/482