Summary for 5KDT
| Entry DOI | 10.2210/pdb5kdt/pdb |
| Related | 5I2K 5I2N |
| Descriptor | Glutamate receptor ionotropic, NMDA 2A, Glutamate receptor ionotropic, NMDA 1, ACETATE ION, ... (7 entities in total) |
| Functional Keywords | nmda, receptor, glutamate, channel, transport protein |
| Biological source | Homo sapiens (Human) More |
| Cellular location | Cell membrane; Multi-pass membrane protein: Q12879 Q05586 |
| Total number of polymer chains | 2 |
| Total formula weight | 66041.53 |
| Authors | Wallweber, H.J.A.,Lupardus, P.J. (deposition date: 2016-06-08, release date: 2016-07-13, Last modification date: 2024-11-06) |
| Primary citation | Volgraf, M.,Sellers, B.D.,Jiang, Y.,Wu, G.,Ly, C.Q.,Villemure, E.,Pastor, R.M.,Yuen, P.W.,Lu, A.,Luo, X.,Liu, M.,Zhang, S.,Sun, L.,Fu, Y.,Lupardus, P.J.,Wallweber, H.J.,Liederer, B.M.,Deshmukh, G.,Plise, E.,Tay, S.,Reynen, P.,Herrington, J.,Gustafson, A.,Liu, Y.,Dirksen, A.,Dietz, M.G.,Liu, Y.,Wang, T.M.,Hanson, J.E.,Hackos, D.,Scearce-Levie, K.,Schwarz, J.B. Discovery of GluN2A-Selective NMDA Receptor Positive Allosteric Modulators (PAMs): Tuning Deactivation Kinetics via Structure-Based Design. J. Med. Chem., 59:2760-2779, 2016 Cited by PubMed Abstract: The N-methyl-D-aspartate receptor (NMDAR) is a Na(+) and Ca(2+) permeable ionotropic glutamate receptor that is activated by the coagonists glycine and glutamate. NMDARs are critical to synaptic signaling and plasticity, and their dysfunction has been implicated in a number of neurological disorders, including schizophrenia, depression, and Alzheimer's disease. Herein we describe the discovery of potent GluN2A-selective NMDAR positive allosteric modulators (PAMs) starting from a high-throughput screening hit. Using structure-based design, we sought to increase potency at the GluN2A subtype, while improving selectivity against related α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). The structure-activity relationship of channel deactivation kinetics was studied using a combination of electrophysiology and protein crystallography. Effective incorporation of these strategies resulted in the discovery of GNE-0723 (46), a highly potent and brain penetrant GluN2A-selective NMDAR PAM suitable for in vivo characterization. PubMed: 26919761DOI: 10.1021/acs.jmedchem.5b02010 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.44 Å) |
Structure validation
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