6Q60

Structure of GluA2 ligand-binding domain (S1S2J) in complex with the agonist (S)-2-Amino-3-(2-methyl-5-hydroxy-2H-1,2,3-triazol-4-yl)propanoic acid at 1.55 A resolution

6Q60 の概要

• エントリーDOI: 10.2210/pdb6q60/pdb
• 分子名称: Glutamate receptor 2, (2~{S})-2-azanyl-3-(2-methyl-5-oxidanyl-1,2,3-triazol-4-yl)propanoic acid, SULFATE ION, ... (7 entities in total)
• 機能のキーワード: ampa receptor, glua2-s1s2, ligand binding domain, agonist, membrane protein
• 由来する生物種: Rattus norvegicus (Rat); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 60539.42

構造登録者

Moellerud, S.,Temperini, P.,Kastrup, J.S. (登録日: 2018-12-10, 公開日: 2019-04-17, 最終更新日: 2024-11-20)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.55 Å)