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Mapping the binding site of the neuroprotectant ifenprodil on NMDA receptors.
Perin-Dureau F
,
Rachline J
,
Neyton J
,
Paoletti P
.
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Ifenprodil is a noncompetitive antagonist of NMDA receptors highly selective for the NMDA receptor 2B (NR2B) subunit. It is widely used as a pharmacological tool to discriminate subpopulations of NMDA receptors, and derivatives are currently being developed as candidate neuroprotectants. Despite numerous studies on the mechanism of action of ifenprodil on NMDA receptors, the structural determinants responsible for the subunit selectivity have not been identified. By combining functional studies on recombinant NMDA receptors and biochemical studies on isolated domains, we now show that ifenprodil binds to the N-terminal leucine/isoleucine/valine-binding protein (LIVBP)-like domain of NR2B. In this domain, several residues, both hydrophilic and hydrophobic, were found to control ifenprodil inhibition. Their location in a modeled three-dimensional structure suggests that ifenprodil binds in the cleft of the LIVBP-like domain of NR2B by a mechanism (Venus-flytrap) resembling that of the binding of Zn on the LIVBP-like domain of NR2A. These results reinforce the proposal that the LIVBP-like domains of NMDA receptors, and possibly of other ionotropic glutamate receptors, bind modulatory ligands. Moreover, they identify the LIVBP-like domain of the NR2B subunit as a promising therapeutic target and provide a framework for designing structurally novel NR2B-selective antagonists.
Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998, Pubmed
Armstrong,
Structure of a glutamate-receptor ligand-binding core in complex with kainate.
1998,
Pubmed
Armstrong,
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core.
2000,
Pubmed
Ayalon,
Functional assembly of AMPA and kainate receptors is mediated by several discrete protein-protein interactions.
2001,
Pubmed
,
Xenbase
Callebaut,
Deciphering protein sequence information through hydrophobic cluster analysis (HCA): current status and perspectives.
1997,
Pubmed
Carter,
Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. II. Evidence for N-methyl-D-aspartate receptor antagonist properties.
1988,
Pubmed
Chen,
Overexpression of a glutamate receptor (GluR2) ligand binding domain in Escherichia coli: application of a novel protein folding screen.
1997,
Pubmed
Chenard,
Antagonists selective for NMDA receptors containing the NR2B subunit.
1999,
Pubmed
Chizh,
NMDA receptor antagonists as analgesics: focus on the NR2B subtype.
2001,
Pubmed
Choi,
Identification and mechanism of action of two histidine residues underlying high-affinity Zn2+ inhibition of the NMDA receptor.
1999,
Pubmed
,
Xenbase
Christine,
Effect of zinc on NMDA receptor-mediated channel currents in cortical neurons.
1990,
Pubmed
Dingledine,
The glutamate receptor ion channels.
1999,
Pubmed
Fayyazuddin,
Four residues of the extracellular N-terminal domain of the NR2A subunit control high-affinity Zn2+ binding to NMDA receptors.
2000,
Pubmed
,
Xenbase
Gallagher,
Interactions between ifenprodil and the NR2B subunit of the N-methyl-D-aspartate receptor.
1996,
Pubmed
He Xl,
Allosteric activation of a spring-loaded natriuretic peptide receptor dimer by hormone.
2001,
Pubmed
Hubbard,
The structural aspects of limited proteolysis of native proteins.
1998,
Pubmed
Kew,
A novel mechanism of activity-dependent NMDA receptor antagonism describes the effect of ifenprodil in rat cultured cortical neurones.
1996,
Pubmed
Kew,
An allosteric interaction between the NMDA receptor polyamine and ifenprodil sites in rat cultured cortical neurones.
1998,
Pubmed
Krupp,
N-terminal domains in the NR2 subunit control desensitization of NMDA receptors.
1998,
Pubmed
Kunishima,
Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor.
2000,
Pubmed
Kuusinen,
Oligomerization and ligand-binding properties of the ectodomain of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunit GluRD.
1999,
Pubmed
Kuusinen,
Molecular dissection of the agonist binding site of an AMPA receptor.
1995,
Pubmed
Legendre,
Ifenprodil blocks N-methyl-D-aspartate receptors by a two-component mechanism.
1991,
Pubmed
Leuschner,
Subtype-specific assembly of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits is mediated by their n-terminal domains.
1999,
Pubmed
Low,
Molecular determinants of coordinated proton and zinc inhibition of N-methyl-D-aspartate NR1/NR2A receptors.
2000,
Pubmed
,
Xenbase
Masuko,
A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor: effects of spermine, protons, and ifenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein.
1999,
Pubmed
,
Xenbase
Mayer,
Mechanisms for ligand binding to GluR0 ion channels: crystal structures of the glutamate and serine complexes and a closed apo state.
2001,
Pubmed
Mott,
Phenylethanolamines inhibit NMDA receptors by enhancing proton inhibition.
1998,
Pubmed
,
Xenbase
O'Hara,
The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmic binding proteins.
1993,
Pubmed
Pahk,
Influence of extracellular pH on inhibition by ifenprodil at N-methyl-D-aspartate receptors in Xenopus oocytes.
1997,
Pubmed
,
Xenbase
Paoletti,
Molecular organization of a zinc binding n-terminal modulatory domain in a NMDA receptor subunit.
2000,
Pubmed
,
Xenbase
Paoletti,
High-affinity zinc inhibition of NMDA NR1-NR2A receptors.
1997,
Pubmed
,
Xenbase
Paoletti,
Glycine-independent and subunit-specific potentiation of NMDA responses by extracellular Mg2+.
1995,
Pubmed
,
Xenbase
Quiocho,
Atomic structure and specificity of bacterial periplasmic receptors for active transport and chemotaxis: variation of common themes.
1996,
Pubmed
Sack,
Periplasmic binding protein structure and function. Refined X-ray structures of the leucine/isoleucine/valine-binding protein and its complex with leucine.
1989,
Pubmed
Sali,
Comparative protein modelling by satisfaction of spatial restraints.
1993,
Pubmed
Stern-Bach,
Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins.
1994,
Pubmed
,
Xenbase
Tamiz,
Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors.
1998,
Pubmed
,
Xenbase
Traynelis,
Control of voltage-independent zinc inhibition of NMDA receptors by the NR1 subunit.
1998,
Pubmed
,
Xenbase
Villarroel,
Glycine-independent NMDA receptor desensitization: localization of structural determinants.
1998,
Pubmed
Westbrook,
Micromolar concentrations of Zn2+ antagonize NMDA and GABA responses of hippocampal neurons.
,
Pubmed
Williams,
Ifenprodil discriminates subtypes of the N-methyl-D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors.
1993,
Pubmed
,
Xenbase
Zheng,
Allosteric interaction between the amino terminal domain and the ligand binding domain of NR2A.
2001,
Pubmed
