4NXO

Crystal Structure of Insulin Degrading Enzyme in complex with BDM44768

4NXO の概要

• エントリーDOI: 10.2210/pdb4nxo/pdb
• 分子名称: Insulin-degrading enzyme, ZINC ION, 4-fluoro-N-({1-[(2R)-4-(hydroxyamino)-1-(naphthalen-2-yl)-4-oxobutan-2-yl]-1H-1,2,3-triazol-4-yl}methyl)benzamide, ... (9 entities in total)
• 機能のキーワード: hydrolase, inhibitor, cysteine free, 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: 232179.28

構造登録者

Liang, W.G.,Deprez, R.,Deprez, B.,Tang, W. (登録日: 2013-12-09, 公開日: 2015-10-07, 最終更新日: 2023-09-20)

主引用文献

Deprez-Poulain, R.,Hennuyer, N.,Bosc, D.,Liang, W.G.,Enee, E.,Marechal, X.,Charton, J.,Totobenazara, J.,Berte, G.,Jahklal, J.,Verdelet, T.,Dumont, J.,Dassonneville, S.,Woitrain, E.,Gauriot, M.,Paquet, C.,Duplan, I.,Hermant, P.,Cantrelle, F.X.,Sevin, E.,Culot, M.,Landry, V.,Herledan, A.,Piveteau, C.,Lippens, G.,Leroux, F.,Tang, W.J.,van Endert, P.,Staels, B.,Deprez, B.
Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice.
Nat Commun, 6:8250-8250, 2015

PubMed Abstract: Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.

PubMed: 26394692
DOI: 10.1038/ncomms9250

実験手法

X-RAY DIFFRACTION (2.73 Å)