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| [[Image:2g56.jpg|left|200px]] | | {{Seed}} |
| | [[Image:2g56.png|left|200px]] |
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| {{STRUCTURE_2g56| PDB=2g56 | SCENE= }} | | {{STRUCTURE_2g56| PDB=2g56 | SCENE= }} |
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| '''crystal structure of human insulin-degrading enzyme in complex with insulin B chain'''
| | ===crystal structure of human insulin-degrading enzyme in complex with insulin B chain=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_17051221}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 17051221 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_17051221}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Tang, W J.]] | | [[Category: Tang, W J.]] |
| [[Category: Protein-peptide complex]] | | [[Category: Protein-peptide complex]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 04:41:59 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Tue Jul 29 04:44:12 2008'' |