alpha-Glucosidase (EC 3.2.1.20) is a critical enzyme with clinical relevance to type 2 diabetes mellitus. Therefore, research on this enzyme's inhibition is important. In the present study, we investigated Zn2+-induced inhibition and the structural changes of alpha-glucosidase. alpha-Glucosidase activity was significantly inhibited by Zn2+ in a dose-dependent manner. The inhibition followed a multi-phase kinetic process with a first-order reaction. Zn2+ inhibited alpha-glucosidase in a parabolic mixed-type reaction (K-i = 0.102 +/- 0.001 mM) and directly induced the unfolding of re-glucosidase, resulting in a slight hydrophobic exposure. We also performed 10 ns molecular dynamics simulations on alpha-glucosidase and Zn2+. The simulations suggest that ten Zn2+ ions possibly interact with 57 alpha-glucosidase residues. The molecular dynamics simulations also confirmed the binding mechanism of Zn2+ to alpha-glucosidase and suggest that the Zn2+ binding sites are not located in the glucose binding pocket of alpha-glucosidase. Our study provides insights into the mechanism of Zn2+-induced unfolding of alpha-glucosidase and inhibition of ligand binding and suggests that Zn2+ could act as a potent inhibitor of alpha-glucosidase for the treatment of type 2 diabetes mellitus. (C) 2012 Elsevier Ltd. All rights reserved.