5EWM

CRYSTAL STRUCTURE OF AMINO TERMINAL DOMAINS OF THE NMDA RECEPTOR SUBUNIT GLUN1 AND GLUN2B IN COMPLEX WITH EVT-101

Summary for 5EWM

• Entry DOI: 10.2210/pdb5ewm/pdb
• Related: 5WMJ 5WML
• Descriptor: NMDA glutamate receptor subunit, Glutamate receptor ionotropic, NMDA 2B, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: glutamate receptor, allosteric modulator, glun2b antagonists, transport protein
• Biological source: Xenopus laevis (African clawed frog); More
• Total number of polymer chains: 4
• Total formula weight: 173209.37

Authors

Pandit, J. (deposition date: 2015-11-20, release date: 2016-03-02, Last modification date: 2024-10-09)

Primary citation

Stroebel, D.,Buhl, D.L.,Knafels, J.D.,Chanda, P.K.,Green, M.,Sciabola, S.,Mony, L.,Paoletti, P.,Pandit, J.
A Novel Binding Mode Reveals Two Distinct Classes of NMDA Receptor GluN2B-selective Antagonists.
Mol.Pharmacol., 89:541-551, 2016

PubMed 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.

PubMed: 26912815
DOI: 10.1124/mol.115.103036

Experimental method

X-RAY DIFFRACTION (2.76 Å)