Article Dans Une Revue Molecular Pharmacology Année : 2016

A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists

Résumé

N-methyl-d-aspartate receptors (NMDARs) are glutamate-gated ion channels that play key roles in brain physiology and pathology. Because numerous pathologic conditions involve NMDAR overactivation, subunit-selective antagonists hold strong therapeutic potential, although clinical successes remain limited. Among the most promising NMDAR-targeting drugs are allosteric inhibitors of GluN2B-containing receptors. Since the discovery of ifenprodil, a range of GluN2B-selective compounds with strikingly different structural motifs have been identified. This molecular diversity raises the possibility of distinct binding sites, although supporting data are lacking. Using X-ray crystallography, we show that EVT-101, a GluN2B antagonist structurally unrelated to the classic phenylethanolamine pharmacophore, binds at the same GluN1/GluN2B dimer interface as ifenprodil but adopts a remarkably different binding mode involving a distinct subcavity and receptor interactions. Mutagenesis experiments demonstrate that this novel binding site is physiologically relevant. Moreover, in silico docking unveils that GluN2B-selective antagonists broadly divide into two distinct classes according to binding pose. These data widen the allosteric and pharmacological landscape of NMDARs and offer a renewed structural framework for designing next-generation GluN2B antagonists with therapeutic value for brain disorders.
Fichier principal
Vignette du fichier
MolPharmacol2016.full.pdf (1.84 Mo) Télécharger le fichier
Origine Publication financée par une institution
Loading...

Dates et versions

inserm-02439012 , version 1 (14-01-2020)

Identifiants

Citer

David Stroebel, Derek Buhl, John Knafels, Pranab Chanda, Michael Green, et al.. A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists. Molecular Pharmacology, 2016, 89 (5), pp.541-551. ⟨10.1124/mol.115.103036⟩. ⟨inserm-02439012⟩
26 Consultations
95 Téléchargements

Altmetric

Partager

More