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Molecular Pharmacology

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Research ArticleArticle

The bioactive protein-ligand conformation of GluN2C-selective positive allosteric modulators bound to the NMDA receptor

Thomas Maxwell Kaiser, Steven A Kell, Hirofumi Kusumoto, Gil Shaulsky, Subhrajit Bhattacharya, Matthew P Epplin, Katie L Strong, Eric J Miller, Bryan D Cox, David S Menaldino, Dennis C Liotta, Stephen F Traynelis and Pieter Buys Burger
Molecular Pharmacology December 14, 2017, mol.117.110940; DOI: https://doi.org/10.1124/mol.117.110940
Thomas Maxwell Kaiser
Emory University
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Steven A Kell
Emory University
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Hirofumi Kusumoto
Emory University
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Gil Shaulsky
Emory University
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Subhrajit Bhattacharya
Emory University
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Matthew P Epplin
Emory University
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Katie L Strong
Emory University
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Eric J Miller
Emory University
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Bryan D Cox
Emory University
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David S Menaldino
Emory University
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Dennis C Liotta
Emory University
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Stephen F Traynelis
Emory University
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Pieter Buys Burger
Emory University
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Abstract

NMDA receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically-relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action. Here we use molecular biology and homology modelling to identify residues that line a candidate binding pocket for GluN2C-selective pyrrolidinones. We also show that occupancy of only one site in diheteromeric receptors is required for potentiation. Both GluN2A and GluN2B can dominate the sensitivity of triheteromeric receptors to eliminate the actions of pyrrolidinones, thus rendering this series uniquely sensitive to subunit stoichiometry. We have experimentally identified NMR-derived conformers in solution, which combined with molecular modelling, allows the prediction of the bioactive binding pose for this series of GluN2C-selective positive allosteric modulator of NMDA receptors. These data advance our understanding of the site and nature of the ligand-protein interaction for GluN2C-selective positive allosteric modulators for NMDA receptors.

  • Computational drug design
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  • Glutamate receptors
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  • N-methyl-D-aspartate (NMDA)
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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Research ArticleArticle

The bioactive protein-ligand conformation of GluN2C-selective positive allosteric modulators bound to the NMDA receptor

Thomas Maxwell Kaiser, Steven A Kell, Hirofumi Kusumoto, Gil Shaulsky, Subhrajit Bhattacharya, Matthew P Epplin, Katie L Strong, Eric J Miller, Bryan D Cox, David S Menaldino, Dennis C Liotta, Stephen F Traynelis and Pieter Buys Burger
Molecular Pharmacology December 14, 2017, mol.117.110940; DOI: https://doi.org/10.1124/mol.117.110940

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Research ArticleArticle

The bioactive protein-ligand conformation of GluN2C-selective positive allosteric modulators bound to the NMDA receptor

Thomas Maxwell Kaiser, Steven A Kell, Hirofumi Kusumoto, Gil Shaulsky, Subhrajit Bhattacharya, Matthew P Epplin, Katie L Strong, Eric J Miller, Bryan D Cox, David S Menaldino, Dennis C Liotta, Stephen F Traynelis and Pieter Buys Burger
Molecular Pharmacology December 14, 2017, mol.117.110940; DOI: https://doi.org/10.1124/mol.117.110940
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