6q54

Structure of GluA2 ligand-binding domain (S1S2J) in complex with the agonist (S)-2-Amino-3-(1-ethyl-4-hydroxy-1H-1,2,3-triazol-5-yl)propanoic acid at 1.4 A resolution

spinqualitylabelsall models 6q54, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6q54 is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.4Å Ligands: CIT, CL, GOL, HJ8, LI, PEG, PGE, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GRIA2_RAT Receptor for glutamate that functions as ligand-gated ion channel in the central nervous system and plays an important role in excitatory synaptic transmission. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. Publication Abstract from PubMed We report a series of glutamate and aspartate analogues designed using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. Compound 6b showed unprecedented selectivity among AMPA receptor subtypes, confirmed also by an unusual binding mode observed on the crystal structures in complex with the AMPA receptor GluA2 agonist binding domain. Here, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. This observation provides a possible explanation for the pharmacological profile. In the structure with 7a, an unusual organization of water molecules around the bioisostere arises compared to previous structures of ligands with other bioisosteres. Aspartate analogue 8 with the hydroxy-1,2,3-triazole moiety directly attached to glycine was unexpectedly able to activate both the glutamate and glycine agonist binding sites of the NMDA receptor. These observations demonstrate novel features that arise when employing a hydroxyl-triazole moiety as bioisostere for the distal carboxylic acid in glutamate receptor agonists. Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands.,Sainas S, Temperini P, Farnsworth JC, Yi F, M Oslash Llerud S, Jensen A, Nielsen B, Passoni A, Kastrup JS, Hansen KB, Boschi D, Pickering DS, Clausen RP, Lolli ML J Med Chem. 2019 Apr 3. doi: 10.1021/acs.jmedchem.8b01986. PMID:30943028 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Glutamate receptor 3D structures

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