2g54

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spinqualitylabelsall models 2g54, resolution 2.25Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of Zn-bound human insulin-degrading enzyme in complex with insulin B chain

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

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.

Disease

Known diseases associated with this structure: Diabetes mellitus, rare form OMIM:[176730], Hyperproinsulinemia, familial OMIM:[176730], MODY, one form OMIM:[176730]

About this Structure

2G54 is a Protein complex structure of sequences from Homo sapiens with and as ligands. Active as Insulysin, with EC number 3.4.24.56 Full crystallographic information is available from OCA.

Reference

Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism., Shen Y, Joachimiak A, Rosner MR, Tang WJ, Nature. 2006 Oct 19;443(7113):870-4. Epub 2006 Oct 11. PMID:17051221

Page seeded by OCA on Thu Feb 21 17:28:17 2008