2jbu | pdb_00002jbu

Crystal structure of human insulin degrading enzyme complexed with co- purified peptides.

spinqualitylabelsall models 2jbu, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2jbu is a 4 chain structure with sequence from "bacillus_coli"_migula_1895 "bacillus coli" migula 1895 and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DIO Activity: Insulysin, with EC number 3.4.24.56 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Insulin-degrading enzyme 3D structures

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