4LZ5: Crystal Structures Of Glur2 Ligand-binding-domain In Complex With Glutamate And Positive Allosteric Modulators

Positive allosteric modulators ("potentiators") of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPAR) enhance excitatory neurotransmission and may improve the cognitive deficits associated with various neurological disorders. The dihydroisoxazole (DHI) series of AMPAR potentiators described herein originated from the identification of 7 by a high-throughput functional activity screen using mouse embryonic stem (mES) cell-derived neuronal precursors. Subsequent structure-based drug design using X-ray crystal structures of the ligand-binding domain of human GluA2 led to the discovery of both PF-04725379 (11), which in tritiated form became a novel ligand for characterizing the binding affinities of subsequent AMPAR potentiators in rat brain homogenate, and PF-04701475 (8a), a prototype used to explore AMPAR-mediated pharmacology in vivo. Lead series optimization provided 16a, a functionally potent compound lacking the potentially bioactivatable aniline within 8a, but retaining desirable in vitro ADME properties.
PDB ID: 4LZ5Download
MMDB ID: 115666
PDB Deposition Date: 2013/7/31
Updated in MMDB: 2013/12
Experimental Method:
x-ray diffraction
Resolution: 1.5  Å
Source Organism:
Similar Structures:
Biological Unit for 4LZ5: dimeric; determined by author and by software (PISA)
Molecular Components in 4LZ5
Label Count Molecule
Proteins (2 molecules)
Glutamate Receptor 2(Gene symbol: Gria2)
Molecule annotation
Chemicals (6 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB