4W93

Human pancreatic alpha-amylase in complex with montbretin A

Summary for 4W93

• Entry DOI: 10.2210/pdb4w93/pdb
• Related: 1bsi 1cpu 1hny 4gqq 4gqr
• Descriptor: Pancreatic alpha-amylase, CALCIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: amylase, glucosyl hydrolase, enzyme inhibitor, diabetes, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 57235.89

Authors

Williams, L.K.,Caner, S.,Brayer, G.D. (deposition date: 2014-08-27, release date: 2015-07-15, Last modification date: 2024-11-06)

Primary citation

Williams, L.K.,Zhang, X.,Caner, S.,Tysoe, C.,Nguyen, N.T.,Wicki, J.,Williams, D.E.,Coleman, J.,McNeill, J.H.,Yuen, V.,Andersen, R.J.,Withers, S.G.,Brayer, G.D.
The amylase inhibitor montbretin A reveals a new glycosidase inhibition motif.
Nat.Chem.Biol., 11:691-696, 2015

PubMed 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.

PubMed: 26214255
DOI: 10.1038/nchembio.1865

Experimental method

X-RAY DIFFRACTION (1.352 Å)