Development and characterization of functional antibodies targeting NMDA receptors

Tajima, Nami, Simorowski, Noriko, Yovanno, Remy A, Regan, Michael C, Michalski, Kevin, Gómez, Ricardo, Lau, Albert Y, Furukawa, Hiro (February 2022) Development and characterization of functional antibodies targeting NMDA receptors. Nature Communications, 13 (1). p. 923. ISSN 2041-1723

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Abstract

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.

Item Type:	Paper
Subjects:	bioinformatics Investigative techniques and equipment > microscopy > Cryo-electron microscopy organism description > animal > Frog bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics Investigative techniques and equipment bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor bioinformatics > genomics and proteomics > small molecules > NMDA receptor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal Investigative techniques and equipment > assays Investigative techniques and equipment > cloning Investigative techniques and equipment > assays > cloning bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > immunoglobulin proteins organism description > animal > mammal Investigative techniques and equipment > microscopy bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > monoclonal antibody bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organism description > animal > mammal > rodent > rat organism description > animal > mammal > rodent > rat organism description > animal > mammal > rodent bioinformatics > genomics and proteomics > small molecules Investigative techniques and equipment > x ray crystallography organism description > animal > Frog > xenopus
CSHL Authors:	Tajima, Nami Simorowski, Noriko Regan, Michael Michalski, Kevin Furukawa, Hiro Gomez, Ricardo
Communities:	CSHL labs > Furukawa lab CSHL Cancer Center Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	17 February 2022
Date Deposited:	23 Feb 2022 15:15
Last Modified:	09 Feb 2024 20:41
PMCID:	PMC8854693
URI:	https://repository.cshl.edu/id/eprint/40522

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