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Zheng Niu Elke Prade Eleni Malideli Kathleen Hille Alexander Jussupow Yonatan G. Mideksa Li-Mei Yan Chen Qian Markus Fleisch Ana C. Messias Riddhiman Sarkar Michael Sattler Don C. Lamb Matthias J. Feige Carlo Camilloni Aphrodite Kapurniotu Bernd Reif 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(14):5820-5830
Designed peptides derived from the islet amyloid polypeptide (IAPP) cross-amyloid interaction surface with Aβ (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of Aβ 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 β-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 Aβ40. Sequestration of substrates into these colloid-like structures provides a mechanistic basis for ISM function and the design of novel potent anti-amyloid molecules. 相似文献
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