9NYZ | pdb_00009nyz

Crystal structure of DCKA/glutamate-bound GluN1/GluN2A agonist binding domains with UCM-101

PDB DOI: https://doi.org/10.2210/pdb9NYZ/pdb

Classification: MEMBRANE PROTEIN
Organism(s): Rattus norvegicus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2025-03-30 Released: 2025-10-29
Deposition Author(s): Lotti, J.S., Syrenne, J.T., Yates-Hansen, C.K., McClelland, L.J., Hansen, K.B.
Funding Organization(s): National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS), National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.71 Å
R-Value Free:
0.202 (Depositor), 0.202 (DCC)
R-Value Work:
0.168 (Depositor), 0.168 (DCC)
R-Value Observed:
0.169 (Depositor)

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

Novel binding mode for negative allosteric NMDA receptor modulators.

Lotti, J.S., Syrenne, J.T., Benton, A.J., Al-Mousawi, A., Cornelison, L.E., Trolinder, C.J., Yi, F., Zhang, Z., Yates-Hansen, C.K., McClelland, L.J., Bosco, J., Rau, A.R., Clausen, R.P., Hansen, K.B.

(2026) J Gen Physiol 158

PubMed: 41335128 Search on PubMedSearch on PubMed Central
DOI: https://doi.org/10.1085/jgp.202513872
Primary Citation of Related Structures:
9NYZ

PubMed Abstract:
NMDA-type ionotropic glutamate receptors mediate excitatory neurotransmission and synaptic plasticity, but aberrant signaling by these receptors is also implicated in brain disorders. Here, we present the binding site and the mechanism of action for UCM-101, a novel negative NMDA receptor modulator that produces full inhibition of NMDA receptor-mediated excitatory postsynaptic currents in hippocampal CA pyramidal neurons from juvenile mouse brain slices. UCM-101 has a 59-fold higher binding affinity at GluN1/2A compared with GluN1/2B receptors and inhibits diheteromeric GluN1/2A and triheteromeric GluN1/2A/2B receptors with IC50 values of 110 and 240 nM, respectively, in the presence of 1 µM glycine. The novel binding mode for UCM-101 is revealed in a high-resolution crystal structure of the GluN1/2A agonist binding domain heterodimer. UCM-101 and its analog TCN-213 inhibit NMDA receptors by negatively modulating co-agonist binding to the GluN1 subunit via an allosteric mechanism that is conserved with previously described GluN2A-selective antagonists, TCN-201 and MPX-004. Despite the shared mechanism of action, the structural determinants that mediate subunit selectivity for UCM-101 are distinct from those of TCN-201 and MPX-004. These findings provide detailed insights into the binding site and mechanism of action of a novel NMDA receptor modulator and open new avenues for the development of NMDA receptor ligands with therapeutic potential.

Organizational Affiliation

Center for Structural and Functional Neuroscience, Division of Biological and Biomedical Sciences, University of Montana, Missoula, MT, USA.

Macromolecule Content

Total Structure Weight: 65.94 kDa
Atom Count: 5,147
Modeled Residue Count: 566
Deposited Residue Count: 575
Unique protein chains: 2

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Glutamate receptor ionotropic, NMDA 1	A	292	Rattus norvegicus	Mutation(s): 0 Gene Names: Grin1, Nmdar1
UniProt
Find proteins for P35439 (Rattus norvegicus) Explore P35439 Go to UniProtKB: P35439
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P35439
Sequence Annotations Expand
Reference Sequence

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 2
Molecule	Chains	Sequence Length	Organism	Details	Image
Glutamate receptor ionotropic, NMDA 2A	B	283	Rattus norvegicus	Mutation(s): 0 Gene Names: Grin2a
UniProt
Find proteins for Q00959 (Rattus norvegicus) Explore Q00959 Go to UniProtKB: Q00959
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	Q00959
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
A1B7E (Subject of Investigation/LOI) Query on A1B7E Download Ideal Coordinates CCD File SDF format, chain D [auth B] MOL2 format, chain D [auth B] mmCIF format, chain D [auth B]	D [auth B]	N-(cyclohexylmethyl)-2-[(5-{[(1R)-1-phenylpropyl]amino}-1,3,4-thiadiazol-2-yl)sulfanyl]acetamide C₂₀ H₂₈ N₄ O S₂ HTAOPHYTYWYDAU-QGZVFWFLSA-N		Interactions Focus chain D [auth B] Interactions & Density Focus chain D [auth B]
DK1 (Subject of Investigation/LOI) Query on DK1 Download Ideal Coordinates CCD File SDF format, chain C [auth A] MOL2 format, chain C [auth A] mmCIF format, chain C [auth A]	C [auth A]	5,7-DICHLORO-4-HYDROXYQUINOLINE-2-CARBOXYLIC ACID C₁₀ H₅ Cl₂ N O₃ BGKFPRIGXAVYNX-UHFFFAOYSA-N		Interactions Focus chain C [auth A] Interactions & Density Focus chain C [auth A]
GLU (Subject of Investigation/LOI) Query on GLU Download Ideal Coordinates CCD File SDF format, chain E [auth B] MOL2 format, chain E [auth B] mmCIF format, chain E [auth B]	E [auth B]	GLUTAMIC ACID C₅ H₉ N O₄ WHUUTDBJXJRKMK-VKHMYHEASA-N		Interactions Focus chain E [auth B] Interactions & Density Focus chain E [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 1.71 Å
R-Value Free: 0.202 (Depositor), 0.202 (DCC)
R-Value Work: 0.168 (Depositor), 0.168 (DCC)
R-Value Observed: 0.169 (Depositor)

Space Group: P 2₁ 2₁ 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 54.474	α = 90
b = 88.329	β = 90
c = 137.273	γ = 90

Software Package:

Software Name	Purpose
autoPROC	data processing
PHASER	phasing
PHENIX	refinement
Coot	model building
autoPROC	data reduction
autoPROC	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History & Funding Information

Deposition Data

Released Date: 2025-10-29

Deposition Author(s):

Funding Organization	Location	Grant Number
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)	United States	R01NS097536
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)	United States	P30GM140963