Structural elements of a pH-sensitive inhibitor binding site in NMDA receptors

• Published in: Nature communications Vol. 10; no. 1; p. 321
• Main Authors: Regan, Michael C., Zhu, Zongjian, Yuan, Hongjie, Myers, Scott J., Menaldino, Dave S., Tahirovic, Yesim A., Liotta, Dennis C., Traynelis, Stephen F., Furukawa, Hiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18-01-2019; Nature Publishing Group; Nature Portfolio
• Subjects: 631/378/2586; 631/535/1266; 9/74; Allosteric properties; Animals; BASIC BIOLOGICAL SCIENCES; Binding Sites; Cages; Crystallography, X-Ray; Glutamic acid receptors (ionotropic); HEK293 Cells; Humanities and Social Sciences; Humans; Hydrogen-Ion Concentration; Hydrophobicity; Inhibition; Inhibitors; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Ion channels in the nervous system; Ischemia; Medical treatment; multidisciplinary; Mutagenesis, Site-Directed; Mutation; N-Methyl-D-aspartic acid receptors; Neurological diseases; Neuroprotection; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Oocytes; Patch-Clamp Techniques; pH effects; Propanolamines - chemistry; Propanolamines - pharmacology; Rats; Receptors; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - chemistry; Science; Science (multidisciplinary); Stroke; Structural members; X-ray crystallography; Xenopus laevis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-08291-1

Context-dependent inhibition of
N
-methyl-D-aspartate (NMDA) receptors has important therapeutic implications for the treatment of neurological diseases that are associated with altered neuronal firing and signaling. This is especially true in stroke, where the proton concentration in the afflicted area can increase by an order of magnitude. A class of allosteric inhibitors, the 93-series, shows greater potency against GluN1-GluN2B NMDA receptors in such low pH environments, allowing targeted therapy only within the ischemic region. Here we map the 93-series compound binding site in the GluN1-GluN2B NMDA receptor amino terminal domain and show that the interaction of the N-alkyl group with a hydrophobic cage of the binding site is critical for pH-dependent inhibition. Mutation of residues in the hydrophobic cage alters pH-dependent potency, and remarkably, can convert inhibitors into potentiators. Our study provides a foundation for the development of highly specific neuroprotective compounds for the treatment of neurological diseases.
Context-dependent inhibition of NMDA receptors has important therapeutic implications for treatment of neurological diseases. Here, the authors use structural biology and biophysics to describe the basis for pH-dependent inhibition for a class of allosteric NMDAR inhibitors, called the 93-series.