7tes

From Proteopedia

Cryo-EM structure of GluN1b-2B NMDAR in complex with Fab5 in Non-active1 conformation

Structural highlights

7tes is a 8 chain structure with sequence from Mus musculus and Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 4.7Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NMDZ1_RAT NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. Plays a key role in synaptic plasticity, synaptogenesis, excitotoxicity, memory acquisition and learning. It mediates neuronal functions in glutamate neurotransmission. Is involved in the cell surface targeting of NMDA receptors.^[1]

Publication Abstract from PubMed

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.

Development and characterization of functional antibodies targeting NMDA receptors.,Tajima N, Simorowski N, Yovanno RA, Regan MC, Michalski K, Gomez R, Lau AY, Furukawa H Nat Commun. 2022 Feb 17;13(1):923. doi: 10.1038/s41467-022-28559-3. PMID:35177668^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Inanobe A, Furukawa H, Gouaux E. Mechanism of partial agonist action at the NR1 subunit of NMDA receptors. Neuron. 2005 Jul 7;47(1):71-84. PMID:15996549 doi:10.1016/j.neuron.2005.05.022
↑ Tajima N, Simorowski N, Yovanno RA, Regan MC, Michalski K, Gómez R, Lau AY, Furukawa H. Development and characterization of functional antibodies targeting NMDA receptors. Nat Commun. 2022 Feb 17;13(1):923. PMID:35177668 doi:10.1038/s41467-022-28559-3