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Journal articles
A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists
Abstract : 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.
Cited literature [70 references]
https://www.hal.inserm.fr/inserm-02439012
Contributor : Mélissa David <>
Submitted on : Tuesday, January 14, 2020 - 2:18:08 PM
Last modification on : Thursday, July 1, 2021 - 5:32:47 PM
Long-term archiving on: : Wednesday, April 15, 2020 - 5:30:49 PM
Contributor : Mélissa David <>
Submitted on : Tuesday, January 14, 2020 - 2:18:08 PM
Last modification on : Thursday, July 1, 2021 - 5:32:47 PM
Long-term archiving on: : Wednesday, April 15, 2020 - 5:30:49 PM
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MolPharmacol2016.full.pdf
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