| Literature DB >> 26214255 |
Leslie K Williams1, Xiaohua Zhang2, Sami Caner1, Christina Tysoe3, Nham T Nguyen1, Jacqueline Wicki2, David E Williams4, John Coleman5, John H McNeill6, Violet Yuen6, Raymond J Andersen4, Stephen G Withers7, Gary D Brayer1.
Abstract
The complex plant flavonol glycoside montbretin A is a potent (Ki = 8 nM) and specific inhibitor of human pancreatic α-amylase with potential as a therapeutic for diabetes and obesity. Controlled degradation studies on montbretin A, coupled with inhibition analyses, identified an essential high-affinity core structure comprising the myricetin and caffeic acid moieties linked via a disaccharide. X-ray structural analyses of the montbretin A-human α-amylase complex confirmed the importance of this core structure and revealed a novel mode of glycosidase inhibition wherein internal π-stacking interactions between the myricetin and caffeic acid organize their ring hydroxyls for optimal hydrogen bonding to the α-amylase catalytic residues D197 and E233. This novel inhibitory motif can be reproduced in a greatly simplified analog, offering potential for new strategies for glycosidase inhibition and therapeutic development.Entities:
Mesh：
Substances：
Year: 2015 PMID： 26214255 DOI： 10.1038/nchembio.1865
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 15.040