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2jbu

From Proteopedia

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{{STRUCTURE_2jbu| PDB=2jbu | SCENE= }}
{{STRUCTURE_2jbu| PDB=2jbu | SCENE= }}
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'''CRYSTAL STRUCTURE OF HUMAN INSULIN DEGRADING ENZYME COMPLEXED WITH CO-PURIFIED PEPTIDES.'''
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===CRYSTAL STRUCTURE OF HUMAN INSULIN DEGRADING ENZYME COMPLEXED WITH CO-PURIFIED PEPTIDES.===
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==Overview==
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Insulin-degrading enzyme (IDE) is a zinc metalloprotease that hydrolyzes amyloid-beta (Abeta) and insulin, which are peptides associated with Alzheimer disease (AD) and diabetes, respectively. Our previous structural analysis of substrate-bound human 113-kDa IDE reveals that the N- and C-terminal domains of IDE, IDE-N and IDE-C, make substantial contact to form an enclosed catalytic chamber to entrap its substrates. Furthermore, IDE undergoes a switch between the closed and open conformations for catalysis. Here we report a substrate-free IDE structure in its closed conformation, revealing the molecular details of the active conformation of the catalytic site of IDE and new insights as to how the closed conformation of IDE may be kept in its resting, inactive conformation. We also show that Abeta is degraded more efficiently by IDE carrying destabilizing mutations at the interface of IDE-N and IDE-C (D426C and K899C), resulting in an increase in Vmax with only minimal changes to Km. Because ATP is known to activate the ability of IDE to degrade short peptides, we investigated the interaction between ATP and activating mutations. We found that these mutations rendered IDE less sensitive to ATP activation, suggesting that ATP might facilitate the transition from the closed state to the open conformation. Consistent with this notion, we found that ATP induced an increase in hydrodynamic radius, a shift in electrophoretic mobility, and changes in secondary structure. Together, our results highlight the importance of the closed conformation for regulating the activity of IDE and provide new molecular details that will facilitate the development of activators and inhibitors of IDE.
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{{ABSTRACT_PUBMED_17613531}}
==About this Structure==
==About this Structure==
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[[Category: Protease]]
[[Category: Protease]]
[[Category: Zinc]]
[[Category: Zinc]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jul 28 06:02:56 2008''

Revision as of 03:02, 28 July 2008

Image:2jbu.png

Template:STRUCTURE 2jbu

CRYSTAL STRUCTURE OF HUMAN INSULIN DEGRADING ENZYME COMPLEXED WITH CO-PURIFIED PEPTIDES.

Template:ABSTRACT PUBMED 17613531

About this Structure

2JBU is a Single protein structure of sequence from Escherichia coli and Homo sapiens. Full crystallographic information is available from OCA.

Reference

Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE., Im H, Manolopoulou M, Malito E, Shen Y, Zhao J, Neant-Fery M, Sun CY, Meredith SC, Sisodia SS, Leissring MA, Tang WJ, J Biol Chem. 2007 Aug 31;282(35):25453-63. Epub 2007 Jul 5. PMID:17613531

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