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Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors.
Mol Pharmacol. 2009 Jan; 75(1):60-74.MP

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.

Authors+Show Affiliations

Laboratoire de Neurobiologie, Centre National de Recherche Scientifique (CNRS) Unité Mixte de Recherche 8544, Ecole Normale Supérieure, Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18923063

Citation

Mony, Laetitia, et al. "Structural Basis of NR2B-selective Antagonist Recognition By N-methyl-D-aspartate Receptors." Molecular Pharmacology, vol. 75, no. 1, 2009, pp. 60-74.
Mony L, Krzaczkowski L, Leonetti M, et al. Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors. Mol Pharmacol. 2009;75(1):60-74.
Mony, L., Krzaczkowski, L., Leonetti, M., Le Goff, A., Alarcon, K., Neyton, J., Bertrand, H. O., Acher, F., & Paoletti, P. (2009). Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors. Molecular Pharmacology, 75(1), 60-74. https://doi.org/10.1124/mol.108.050971
Mony L, et al. Structural Basis of NR2B-selective Antagonist Recognition By N-methyl-D-aspartate Receptors. Mol Pharmacol. 2009;75(1):60-74. PubMed PMID: 18923063.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Structural basis of NR2B-selective antagonist recognition by N-methyl-D-aspartate receptors. AU - Mony,Laetitia, AU - Krzaczkowski,Lucie, AU - Leonetti,Manuel, AU - Le Goff,Anne, AU - Alarcon,Karine, AU - Neyton,Jacques, AU - Bertrand,Hughes-Olivier, AU - Acher,Francine, AU - Paoletti,Pierre, Y1 - 2008/10/15/ PY - 2008/10/17/pubmed PY - 2009/1/27/medline PY - 2008/10/17/entrez SP - 60 EP - 74 JF - Molecular pharmacology JO - Mol Pharmacol VL - 75 IS - 1 N2 - 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. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/18923063/Structural_basis_of_NR2B_selective_antagonist_recognition_by_N_methyl_D_aspartate_receptors_ DB - PRIME DP - Unbound Medicine ER -