2JBU

Crystal structure of human insulin degrading enzyme complexed with co- purified peptides.

2JBU の概要

• エントリーDOI: 10.2210/pdb2jbu/pdb
• 分子名称: INSULIN-DEGRADING ENZYME, CO-PURIFIED PEPTIDE, 1,4-DIETHYLENE DIOXIDE, ... (4 entities in total)
• 機能のキーワード: metal-binding, metalloprotease, zinc, protease, hydrolase, enzyme assay, insulin degrading enzyme
• 由来する生物種: Homo sapiens; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 231348.39

構造登録者

Im, H.,Shen, Y.,Tang, W.J. (登録日: 2006-12-11, 公開日: 2007-07-03, 最終更新日: 2023-12-13)

主引用文献

Im, H.,Manolopoulou, M.,Malito, E.,Shen, Y.,Zhao, J.,Neant-Fery, M.,Sun, C.-Y.,Meredith, S.C.,Sisodia, S.S.,Leissring, M.A.,Tang, W.J.
Structure of Substrate-Free Human Insulin Degrading Enzyme (Ide) and Biophysical Analysis of ATP-Induced Conformational Switch of Ide
J.Biol.Chem., 282:25453-, 2007

PubMed Abstract: Insulin-degrading enzyme (IDE) is a zinc metalloprotease that hydrolyzes amyloid-beta (Abeta) and insulin, which are peptides associated with Alzheimer disease (AD) and diabetes, respectively. Our previous structural analysis of substrate-bound human 113-kDa IDE reveals that the N- and C-terminal domains of IDE, IDE-N and IDE-C, make substantial contact to form an enclosed catalytic chamber to entrap its substrates. Furthermore, IDE undergoes a switch between the closed and open conformations for catalysis. Here we report a substrate-free IDE structure in its closed conformation, revealing the molecular details of the active conformation of the catalytic site of IDE and new insights as to how the closed conformation of IDE may be kept in its resting, inactive conformation. We also show that Abeta is degraded more efficiently by IDE carrying destabilizing mutations at the interface of IDE-N and IDE-C (D426C and K899C), resulting in an increase in Vmax with only minimal changes to Km. Because ATP is known to activate the ability of IDE to degrade short peptides, we investigated the interaction between ATP and activating mutations. We found that these mutations rendered IDE less sensitive to ATP activation, suggesting that ATP might facilitate the transition from the closed state to the open conformation. Consistent with this notion, we found that ATP induced an increase in hydrodynamic radius, a shift in electrophoretic mobility, and changes in secondary structure. Together, our results highlight the importance of the closed conformation for regulating the activity of IDE and provide new molecular details that will facilitate the development of activators and inhibitors of IDE.

PubMed: 17613531
DOI: 10.1074/JBC.M701590200

実験手法

X-RAY DIFFRACTION (3 Å)