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Structural insight into IAPP-derived amyloid inhibitors and their mechanism of action.
Angew. Chem.-Int. Edit. 59, 2-13 (2020)
Publ. Version/Full Text
Research data
DOI
PMC
Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with A beta (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of A beta amyloid self-assembly. However, the molecular mechanism of their function is not well understood. Using solution-state and solid-state NMR spectroscopy in combination with ensemble-averaged dynamics simulations and other biophysical methods including TEM, fluorescence spectroscopy and microscopy, and DLS, we characterize ISM structural preferences and interactions. We find that the ISM peptide R3-GI is highly dynamic, can adopt a beta-like structure, and oligomerizes into colloid-like assemblies in a process that is reminiscent of liquid-liquid phase separation (LLPS). Our results suggest that such assemblies yield multivalent surfaces for interactions with A beta 40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Amyloid Formation ; Amyloid Inhibitors ; A Beta ; Solid-state Nmr Spectroscopy ; Peptides; Alzheimers-disease; A-beta; Molecular-structure; Liquid Droplets; Peptide; Nmr; Fibrils; State; Identification; Validation
ISSN (print) / ISBN
1433-7851
e-ISSN
1521-3773
Quellenangaben
Volume: 59,
Issue: 14,
Pages: 2-13
Publisher
Wiley
Publishing Place
Weinheim
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Institute of Structural Biology (STB)