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Research ArticleArticle

Structural Basis of NR2B-Selective Antagonist Recognition by N-Methyl-d-aspartate Receptors

Laetitia Mony, Lucie Krzaczkowski, Manuel Leonetti, Anne Le Goff, Karine Alarcon, Jacques Neyton, Hughes-Olivier Bertrand, Francine Acher and Pierre Paoletti
Molecular Pharmacology January 2009, 75 (1) 60-74; DOI: https://doi.org/10.1124/mol.108.050971
Laetitia Mony
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Lucie Krzaczkowski
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Manuel Leonetti
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Anne Le Goff
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Karine Alarcon
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Jacques Neyton
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Hughes-Olivier Bertrand
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Francine Acher
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Pierre Paoletti
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Abstract

N-Methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors endowed with unique pharmacological and functional properties. In particular, their high permeability to calcium ions confers on NMDARs a central role in triggering long term changes in synaptic strength. Under excitotoxic pathological conditions, such as those occurring during brain trauma, stroke, or Parkinson's or Huntington's diseases, calcium influx through NMDAR channels can also lead to neuronal injury. This argues for the use of NMDAR antagonists as potential therapeutic agents. To date, the most promising NMDAR antagonists are ifenprodil and derivatives, compounds that act as noncompetitive inhibitors selective for NMDARs containing the NR2B subunit. Recent studies have identified the large N-terminal domain (NTD) of NR2B as the region controlling ifenprodil sensitivity of NMDARs. We present here a detailed characterization of the ifenprodil binding site using both experimental and computational approaches. 3D homology modeling reveals that ifenprodil fits well in a closed cleft conformation of the NRB NTD; however, ifenprodil can adopt either of two possible binding orientations of opposite direction. By studying the effects of cleft mutations, we show that only the orientation in which the phenyl moiety points deep toward the NTD hinge is functionally relevant. Moreover, based on our model, we identify novel NTD NR2B residues that are crucial for conferring ifenprodil sensitivity and provide functional evidence that these residues directly interact with the ifenprodil molecule. This work provides a general insight into the origin of the subunit-selectivity of NMDAR noncompetitive antagonists and offer clues for the discovery of novel NR2B-selective antagonists.

Footnotes

  • This work was supported by Ministère de la Recherche (to L.M.) and by Institut National de la Santé et de la Recherche Médicale and l'Agence Nationale de la Recherche (to P.P.)

  • ABBREVIATIONS: NMDAR, N-methyl-d-aspartate receptor; NMDA, N-methyl-d-aspartate; NTD, N-terminal domain; LIVBP, leucine/isoleucine/valine-binding protein; 3D, three-dimensional; wt, wild type; ABD, agonist-binding domain.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • ↵1 Current affiliation: Laboratory of Molecular Neurobiology and Biophysics, Rockefeller University and Howard Hughes Medical Institute, New York, New York.

    • Received July 31, 2008.
    • Accepted October 14, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (1)
Molecular Pharmacology
Vol. 75, Issue 1
1 Jan 2009
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Research ArticleArticle

Structural Basis of NR2B-Selective Antagonist Recognition by N-Methyl-d-aspartate Receptors

Laetitia Mony, Lucie Krzaczkowski, Manuel Leonetti, Anne Le Goff, Karine Alarcon, Jacques Neyton, Hughes-Olivier Bertrand, Francine Acher and Pierre Paoletti
Molecular Pharmacology January 1, 2009, 75 (1) 60-74; DOI: https://doi.org/10.1124/mol.108.050971

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Research ArticleArticle

Structural Basis of NR2B-Selective Antagonist Recognition by N-Methyl-d-aspartate Receptors

Laetitia Mony, Lucie Krzaczkowski, Manuel Leonetti, Anne Le Goff, Karine Alarcon, Jacques Neyton, Hughes-Olivier Bertrand, Francine Acher and Pierre Paoletti
Molecular Pharmacology January 1, 2009, 75 (1) 60-74; DOI: https://doi.org/10.1124/mol.108.050971
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