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2g47
From Proteopedia
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Crystal structure of human insulin-degrading enzyme in complex with amyloid-beta (1-40)
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.
About this Structure
2G47 is a Single protein structure of sequence from Homo sapiens with as ligand. 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 Fri Feb 15 17:27:02 2008
