2G49

Crystal structure of human insulin-degrading enzyme in complex with glucagon

2G49 の概要

• エントリーDOI: 10.2210/pdb2g49/pdb
• 関連するPDBエントリー: 2G47 2G48 2G54 2G56
• 分子名称: Insulin-degrading enzyme, glucagon preproprotein, 1,4-DIETHYLENE DIOXIDE, ... (4 entities in total)
• 機能のキーワード: protein-peptide complex, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 236580.05

構造登録者

Shen, Y.,Tang, W.-J. (登録日: 2006-02-21, 公開日: 2006-10-24, 最終更新日: 2024-02-14)

主引用文献

Shen, Y.,Joachimiak, A.,Rosner, M.R.,Tang, W.J.
Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism.
Nature, 443:870-874, 2006

PubMed Abstract: Insulin-degrading enzyme (IDE), a Zn2+-metalloprotease, is involved in the clearance of insulin and amyloid-beta (refs 1-3). Loss-of-function mutations of IDE in rodents cause glucose intolerance and cerebral accumulation of amyloid-beta, whereas enhanced IDE activity effectively reduces brain amyloid-beta (refs 4-7). Here we report structures of human IDE in complex with four substrates (insulin B chain, amyloid-beta peptide (1-40), amylin and glucagon). The amino- and carboxy-terminal domains of IDE (IDE-N and IDE-C, respectively) form an enclosed cage just large enough to encapsulate insulin. Extensive contacts between IDE-N and IDE-C keep the degradation chamber of IDE inaccessible to substrates. Repositioning of the IDE domains enables substrate access to the catalytic cavity. IDE uses size and charge distribution of the substrate-binding cavity selectively to entrap structurally diverse polypeptides. The enclosed substrate undergoes conformational changes to form beta-sheets with two discrete regions of IDE for its degradation. Consistent with this model, mutations disrupting the contacts between IDE-N and IDE-C increase IDE catalytic activity 40-fold. The molecular basis for substrate recognition and allosteric regulation of IDE could aid in designing IDE-based therapies to control cerebral amyloid-beta and blood sugar concentrations.

PubMed: 17051221
DOI: 10.1038/nature05143

実験手法

X-RAY DIFFRACTION (2.5 Å)