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

Summary for 6Q54

• Entry DOI: 10.2210/pdb6q54/pdb
• Descriptor: Glutamate receptor 2, SULFATE ION, (2~{S})-2-azanyl-3-(3-ethyl-5-oxidanyl-1,2,3-triazol-4-yl)propanoic acid, ... (10 entities in total)
• Functional Keywords: ionotropic glutamate receptor, ampa receptor, ligand-binding domain, glua2-s1s2, glua2, glur2, agonist, membrane protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 2
• Total formula weight: 61012.63

Authors

Moellerud, S.,Temperini, P.,Kastrup, J.S. (deposition date: 2018-12-07, release date: 2019-04-17, Last modification date: 2024-10-23)

Primary citation

Sainas, S.,Temperini, P.,Farnsworth, J.C.,Yi, F.,Mollerud, S.,Jensen, A.A.,Nielsen, B.,Passoni, A.,Kastrup, J.S.,Hansen, K.B.,Boschi, D.,Pickering, D.S.,Clausen, R.P.,Lolli, M.L.
Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands.
J.Med.Chem., 62:4467-4482, 2019

PubMed Abstract: 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 ( S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtypes, confirmed also by an unusual binding mode observed for 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 N-methyl-d-aspartic acid receptor. These observations demonstrate novel features that arise when employing a hydroxytriazole moiety as a bioisostere for the distal carboxylic acid in glutamate receptor agonists.

PubMed: 30943028
DOI: 10.1021/acs.jmedchem.8b01986

Experimental method

X-RAY DIFFRACTION (1.4 Å)