2G54

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

Summary for 2G54

• Entry DOI: 10.2210/pdb2g54/pdb
• Related: 2G47 2G48 2G49 2G56
• Descriptor: Insulin-degrading enzyme, insulin, ZINC ION, ... (5 entities in total)
• Functional Keywords: protein-peptide complex, hydrolase
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P01308
• Total number of polymer chains: 4
• Total formula weight: 236605.22

Authors

Shen, Y.,Tang, W.-J. (deposition date: 2006-02-22, release date: 2006-10-24, Last modification date: 2024-02-14)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.25 Å)