8Y1V
Structure of GluN1b-GluN2D NMDA receptor in complex with competitive antagonist R-CPP and allosteric inhibitor YY-23
This is a non-PDB format compatible entry.
Summary for 8Y1V
| Entry DOI | 10.2210/pdb8y1v/pdb |
| EMDB information | 38847 |
| Descriptor | Isoform 6 of Glutamate receptor ionotropic, NMDA 1, Glutamate receptor ionotropic, NMDA 2D, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total) |
| Functional Keywords | ion channel, calcium permeable, glutamate receptor, neuronal expression, membrane protein, membrane protein-inhibitor complex, membrane protein/inhibitor |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 395740.92 |
| Authors | Zhang, J.L.,Zhu, S.J.,Guo, F. (deposition date: 2024-01-25, release date: 2025-01-22, Last modification date: 2026-02-04) |
| Primary citation | Zhang, J.,Duan, J.,Li, W.,Wang, X.,Ren, S.,Ye, L.,Liu, F.,Tian, X.,Xie, Y.,Huang, Y.,Sun, Y.,Song, N.,Li, T.,Cai, X.,Liu, Z.,Zhou, H.,Huang, C.,Li, Y.,Zhu, S.,Guo, F. An antidepressant mechanism underlying the allosteric inhibition of GluN2D-incorporated NMDA receptors at GABAergic interneurons. Sci Adv, 11:eadq0444-eadq0444, 2025 Cited by PubMed Abstract: -methyl-d-aspartate receptors (NMDARs), key excitatory ion channels, have gained attention as anti-depression targets. NMDARs consist of two GluN1 and two GluN2 subunits (2A-2D), which determine their pharmacological properties. Few compounds selectively targeting GluN2 subunits with antidepressant effects have been identified. Here, we present YY-23, a compound that selectively inhibits GluN2C- or GluN2D-containing NMDARs. Cryo-EM analysis revealed that YY-23 binds to the transmembrane domain of the GluN2D subunit. YY-23 primarily affects GluN2D-containing NMDARs on GABAergic interneurons in the prefrontal cortex, suppressing GABAergic neurotransmission and enhancing excitatory transmission. Behavioral assays demonstrate YY-23's rapid antidepressant effects in both stress-naïve and stress-exposed models, which are lost in mice with global or selective knockout of the gene in parvalbumin-positive interneurons. These findings highlight GluN2D-containing NMDARs on GABAergic interneurons as potential depression treatment targets. PubMed: 40043126DOI: 10.1126/sciadv.adq0444 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (4.2 Å) |
Structure validation
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