2WBY

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

2WBY の概要

• エントリーDOI: 10.2210/pdb2wby/pdb
• 関連するPDBエントリー: 1A7F 1AI0 1AIY 1B9E 1BEN 1EFE 1EV3 1EV6 1EVR 1FU2 1FUB 1G7A 1G7B 1GUJ 1HIQ 1HIS 1HIT 1HLS 1HTV 1HUI 1IOG 1IOH 1J73 1JCA 1JCO 1K3M 1KMF 1LKQ 1LPH 1MHI 1MHJ 1MSO 1OS3 1OS4 1Q4V 1QIY 1QIZ 1QJ0 1RWE 1SF1 1SJT 1T0C 1T1K 1T1P 1T1Q 1TRZ 1TYL 1TYM 1UZ9 1VKT 1W8P 1XDA 1XGL 1XW7 1ZEG 1ZEH 1ZNJ 2AIY 2C8Q 2C8R 2CEU 2H67 2HH4 2HHO 2HIU 2JBU 2JG4 2VJZ 2VK0 2WC0 3AIY 4AIY 5AIY
• 分子名称: INSULIN-DEGRADING ENZYME, INSULIN A CHAIN, INSULIN B CHAIN, ... (5 entities in total)
• 機能のキーワード: hydrolase/hormone, glucose metabolism, carbohydrate metabolism, disease mutation, diabetes mellitus, zinc, dioxane, insulin, hormone, secreted, protease, disulfide bond, pharmaceutical, metalloprotease, human insulin-degradng enzyme, hydrolase, cytoplasm, polymorphism, metal-binding, cleavage on pair of basic residues, hydrolase-hormone complex
• 由来する生物種: HOMO SAPIENS (HUMAN); 詳細
• 細胞内の位置: Cytoplasm: P14735; Secreted: P01308 P01308
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 238086.20

構造登録者

Manolopoulou, M.,Guo, Q.,Malito, E.,Schilling, A.B.,Tang, W.J. (登録日: 2009-03-06, 公開日: 2009-03-24, 最終更新日: 2024-11-13)

主引用文献

Manolopoulou, M.,Guo, Q.,Malito, E.,Schilling, A.B.,Tang, W.J.
Molecular Basis of Catalytic Chamber-Assisted Unfolding and Cleavage of Human Insulin by Human Insulin Degrading Enzyme.
J.Biol.Chem., 284:14177-, 2009

PubMed Abstract: Insulin is a hormone vital for glucose homeostasis, and insulin-degrading enzyme (IDE) plays a key role in its clearance. IDE exhibits a remarkable specificity to degrade insulin without breaking the disulfide bonds that hold the insulin A and B chains together. Using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry to obtain high mass accuracy, and electron capture dissociation (ECD) to selectively break the disulfide bonds in gas phase fragmentation, we determined the cleavage sites and composition of human insulin fragments generated by human IDE. Our time-dependent analysis of IDE-digested insulin fragments reveals that IDE is highly processive in its initial cleavage at the middle of both the insulin A and B chains. This ensures that IDE effectively splits insulin into inactive N- and C-terminal halves without breaking the disulfide bonds. To understand the molecular basis of the recognition and unfolding of insulin by IDE, we determined a 2.6-A resolution insulin-bound IDE structure. Our structure reveals that IDE forms an enclosed catalytic chamber that completely engulfs and intimately interacts with a partially unfolded insulin molecule. This structure also highlights how the unique size, shape, charge distribution, and exosite of the IDE catalytic chamber contribute to its high affinity ( approximately 100 nm) for insulin. In addition, this structure shows how IDE utilizes the interaction of its exosite with the N terminus of the insulin A chain as well as other properties of the catalytic chamber to guide the unfolding of insulin and allowing for the processive cleavages.

PubMed: 19321446
DOI: 10.1074/JBC.M900068200

実験手法

X-RAY DIFFRACTION (2.6 Å)