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

Feng Yi; Tung Chung Mou; Katherine N. Dorsett; Robert A. Volkmann; Frank S. Menniti; Stephen R. Sprang; Kasper B. Hansen

doi:10.1016/j.neuron.2016.08.014

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

Feng Yi
, Tung Chung Mou
, Katherine N. Dorsett
, Robert A. Volkmann
, Frank S. Menniti
, Stephen R. Sprang
, Kasper B. Hansen

University of Montana
BioPharmaWorks, LLC
University of Rhode Island

Research output: Contribution to journal › Article › peer-review

93 Scopus citations

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.

Original language	English
Pages (from-to)	1316-1329
Number of pages	14
Journal	Neuron
Volume	91
Issue number	6
DOIs	https://doi.org/10.1016/j.neuron.2016.08.014
State	Published - Sep 21 2016

Funding

We thank the staff at the Advanced Photon System (APS), Argonne National Laboratory, and the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory, for their excellent beamline support. The use of SSRL and APS is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515 and DE-AC02-06-CH11357. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research and by the National Institutes of Health (P41GM103393). We thank Hiro Furukawa for providing DNA constructs for expression and purification of GluN1 and GluN2A LBDs, Gabriella K. Popescu for providing the DNA construct for GluN1-CC, and Gina C. Bullard, Marlene E. Woldstad, and Cindee K. Yates-Hansen for excellent technical assistance. We thank Christopher M. Fanger, David R. Anderson, and Ethan Magno for discussion and critical comments. This work was supported by the National Institutes of Health (P20GM103546 and R01NS097536) and a small research grant from Mnemosyne Pharmaceuticals, Inc., which is now Luc Therapeutics, Inc., and holds the patent on MPX-004 and MPX-007. K.B.H. was a paid consultant for Luc Therapeutics and R.A.V. and F.S.M. are shareholders in Luc Therapeutics.

Funders	Funder number
R01NS097536, P20GM103546, MPX-004, MPX-007
P41GM103393
DE-AC02-06-CH11357, DE-AC02-76SF00515
Biological and Environmental Research

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title = "Structural Basis for Negative Allosteric Modulation of GluN2A-Containing NMDA Receptors",

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.",

author = "Feng Yi and Mou, \{Tung Chung\} and Dorsett, \{Katherine N.\} and Volkmann, \{Robert A.\} and Menniti, \{Frank S.\} and Sprang, \{Stephen R.\} and Hansen, \{Kasper B.\}",

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AU - Mou, Tung Chung

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AU - Menniti, Frank S.

AU - Sprang, Stephen R.

AU - Hansen, Kasper B.

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N2 - 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.

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

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