期刊
NATURE CHEMISTRY
卷 4, 期 5, 页码 355-360出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEM.1293
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资金
- National Institutes of Health [DK79895, GM078114, DK088184]
- National Science Foundation (CRC) [CHE 0832584]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [0832584] Funding Source: National Science Foundation
- Division Of Materials Research
- Direct For Mathematical & Physical Scien [1121288] Funding Source: National Science Foundation
Amyloid formation has been implicated in the pathology of over 20 human diseases, but the rational design of amyloid inhibitors is hampered by a lack of structural information about amyloid-inhibitor complexes. We use isotope labelling and two-dimensional infrared spectroscopy to obtain a residue-specific structure for the complex of human amylin (the peptide responsible for islet amyloid formation in type 2 diabetes) with a known inhibitor (rat amylin). Based on its sequence, rat amylin should block formation of the C-terminal beta-sheet, but at 8 h after mixing, rat amylin blocks the N-terminal beta-sheet instead. At 24 h after mixing, rat amylin blocks neither beta-sheet and forms its own beta-sheet, most probably on the outside of the human fibrils. This is striking, because rat amylin is natively disordered and not previously known to form amyloid beta-sheets. The results show that even seemingly intuitive inhibitors may function by unforeseen and complex structural processes.
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