9mum

From Proteopedia

Crystal structure of GluN1/GluN2A ligand-binding domain in complex with Compound 11, Glycine and Glutamate

Structural highlights

9mum is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.97Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

NMDZ1_HUMAN Defects in GRIN1 are the cause of mental retardation autosomal dominant type 8 (MRD8) [MIM:614254. Mental retardation is characterized by significantly below average general intellectual functioning associated with impairments in adaptative behavior and manifested during the developmental period.^[1]

Function

NMDZ1_HUMAN NMDA receptor subtype of glutamate-gated ion channels with high calcium permeability and voltage-dependent sensitivity to magnesium. Mediated by glycine. This protein 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 (By similarity).

Publication Abstract from PubMed

N-Methyl-d-aspartate receptors are ionotropic glutamate receptors that mediate fast excitatory neurotransmission in the central nervous system. These receptors play essential roles in synaptic plasticity, learning, and memory and are implicated in various neuropathological and psychiatric disorders. Selective modulation of NMDAR subtypes, particularly GluN2A, has proven challenging. The TCN-201 derivatives MPX-004 and MPX-007 are potent and selective for GluN2A receptors, yet their physical properties limit their in vivo utility. In this study, we optimized the MPX-004/MPX-007 scaffold by modifying the linker region between the distal halogenated aromatic ring and the central pyrazine nucleus, resulting in the identification of potent and selective compounds with improved drug-like properties. Notably, compound 1 was used to develop the first GluN2A NAM-based radioligand, and compound 11 showed improved pharmacokinetics and dose-dependent receptor occupancy in vivo. Thus, we provide an array of powerful new tools for the study of GluN2A receptors.

Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration.,Bischoff FP, Van Brandt S, Viellevoye M, De Cleyn M, Surkyn M, Carbajo RJ, Dominguez Blanco M, Wroblowski B, Karpowich NK, Steele RA, Schalk-Hihi C, Miller R, Duda D, Shaffer P, Ballentine S, Simavorian S, Lord B, Neff RA, Bonaventure P, Gijsen HJM J Med Chem. 2025 Feb 27;68(4):4672-4693. doi: 10.1021/acs.jmedchem.4c02751. Epub , 2025 Feb 17. PMID:39960408^[2]

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

References

↑ Hamdan FF, Gauthier J, Araki Y, Lin DT, Yoshizawa Y, Higashi K, Park AR, Spiegelman D, Dobrzeniecka S, Piton A, Tomitori H, Daoud H, Massicotte C, Henrion E, Diallo O, Shekarabi M, Marineau C, Shevell M, Maranda B, Mitchell G, Nadeau A, D'Anjou G, Vanasse M, Srour M, Lafreniere RG, Drapeau P, Lacaille JC, Kim E, Lee JR, Igarashi K, Huganir RL, Rouleau GA, Michaud JL. Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability. Am J Hum Genet. 2011 Mar 11;88(3):306-16. doi: 10.1016/j.ajhg.2011.02.001. Epub, 2011 Mar 3. PMID:21376300 doi:10.1016/j.ajhg.2011.02.001
↑ Bischoff FP, Van Brandt S, Viellevoye M, De Cleyn M, Surkyn M, Carbajo RJ, Dominguez Blanco M, Wroblowski B, Karpowich NK, Steele RA, Schalk-Hihi C, Miller R, Duda D, Shaffer P, Ballentine S, Simavorian S, Lord B, Neff RA, Bonaventure P, Gijsen HJM. Design, Synthesis, and Characterization of GluN2A Negative Allosteric Modulators Suitable for In Vivo Exploration. J Med Chem. 2025 Feb 27;68(4):4672-4693. PMID:39960408 doi:10.1021/acs.jmedchem.4c02751