4GS8

Structure analysis of cysteine free insulin degrading enzyme (ide) with compound bdm43079 [{[(s)-2-(1h-imidazol-4-yl)-1-methylcarbamoyl-ethylcarbamoyl]-methyl}-(3-phenyl-propyl)-amino]-acetic acid

4GS8 の概要

• エントリーDOI: 10.2210/pdb4gs8/pdb
• 関連するPDBエントリー: 4GSC 4GSE 4GSF
• 分子名称: Insulin-degrading enzyme, N-(carboxymethyl)-N-(3-phenylpropyl)glycyl-N-methyl-L-histidinamide, ZINC ION, ... (4 entities in total)
• 機能のキーワード: insulin degrading enzyme, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P14735
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 230054.89

構造登録者

Guo, Q.,Deprez-Poulain, R.,Deprez, B.,Tang, W.J. (登録日: 2012-08-27, 公開日: 2013-08-28, 最終更新日: 2023-09-13)

主引用文献

Charton, J.,Gauriot, M.,Guo, Q.,Hennuyer, N.,Marechal, X.,Dumont, J.,Hamdane, M.,Pottiez, V.,Landry, V.,Sperandio, O.,Flipo, M.,Buee, L.,Staels, B.,Leroux, F.,Tang, W.J.,Deprez, B.,Deprez-Poulain, R.
Imidazole-derived 2-[N-carbamoylmethyl-alkylamino]acetic acids, substrate-dependent modulators of insulin-degrading enzyme in amyloid-beta hydrolysis.
Eur.J.Med.Chem., 79:184-193, 2014

PubMed Abstract: Insulin degrading enzyme (IDE) is a highly conserved zinc metalloprotease that is involved in the clearance of various physiologically peptides like amyloid-beta and insulin. This enzyme has been involved in the physiopathology of diabetes and Alzheimer's disease. We describe here a series of small molecules discovered by screening. Co-crystallization of the compounds with IDE revealed a binding both at the permanent exosite and at the discontinuous, conformational catalytic site. Preliminary structure-activity relationships are described. Selective inhibition of amyloid-beta degradation over insulin hydrolysis was possible. Neuroblastoma cells treated with the optimized compound display a dose-dependent increase in amyloid-beta levels.

PubMed: 24735644
DOI: 10.1016/j.ejmech.2014.04.009

実験手法

X-RAY DIFFRACTION (2.99 Å)