Development and characterization of functional antibodies targeting NMDA receptors

• Published in: Nature communications Vol. 13; no. 1; p. 923
• Main Authors: Tajima, Nami, Simorowski, Noriko, Yovanno, Remy A., Regan, Michael C., Michalski, Kevin, Gómez, Ricardo, Lau, Albert Y., Furukawa, Hiro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.02.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/1; 101/28; 631/1647/664/2229; 631/378/2586; 631/535/1258/1259; 631/535/1266; 9/74; Animals; Antibodies; Antibodies, Monoclonal - genetics; Antibodies, Monoclonal - isolation & purification; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - ultrastructure; Biochemical analysis; Channel gating; Chemical compounds; Cloning, Molecular; Cryoelectron Microscopy; Crystallography; Crystallography, X-Ray; Electrophysiology; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Humanities and Social Sciences; Immunoglobulin Fab Fragments - genetics; Immunoglobulin Fab Fragments - isolation & purification; Immunoglobulin Fab Fragments - pharmacology; Immunoglobulin Fab Fragments - ultrastructure; Immunoglobulin Variable Region - genetics; Immunoglobulin Variable Region - isolation & purification; Immunoglobulin Variable Region - pharmacology; Immunoglobulin Variable Region - ultrastructure; Invasiveness; Ion channels; Molecular dynamics; Molecular Dynamics Simulation; multidisciplinary; N-Methyl-D-aspartic acid receptors; Neurodegeneration; Neurological diseases; Neurological disorders; Oocytes; Rats; Reagents; Receptors; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - isolation & purification; Recombinant Proteins - genetics; Recombinant Proteins - isolation & purification; Recombinant Proteins - pharmacology; Recombinant Proteins - ultrastructure; Science; Science (multidisciplinary); Sf9 Cells; Spodoptera; Tumors; X-ray crystallography; Xenopus laevis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28559-3

N -methyl-D-aspartate receptors (NMDARs) are critically involved in basic brain functions and neurodegeneration as well as tumor invasiveness. Targeting specific subtypes of NMDARs with distinct activities has been considered an effective therapeutic strategy for neurological disorders and diseases. However, complete elimination of off-target effects of small chemical compounds has been challenging and thus, there is a need to explore alternative strategies for targeting NMDAR subtypes. Here we report identification of a functional antibody that specifically targets the GluN1-GluN2B NMDAR subtype and allosterically down-regulates ion channel activity as assessed by electrophysiology. Through biochemical analysis, x-ray crystallography, single-particle electron cryomicroscopy, and molecular dynamics simulations, we show that this inhibitory antibody recognizes the amino terminal domain of the GluN2B subunit and increases the population of the non-active conformational state. The current study demonstrates that antibodies may serve as specific reagents to regulate NMDAR functions for basic research and therapeutic objectives. Selective targeting individual subtypes of N-methyl-D-aspartate receptors (NMDARs) is a desirable therapeutic strategy for neurological disorders. Here, the authors report identification of a functional antibody that specifically targets and allosterically down-regulates ion channel activity of the GluN1—GluN2B NMDAR subtype.