Download MendeleyStructures of human pancreatic alpha-amylase in complex with acarviostatins: Implications for drug design against type II diabetes
Qin, X., Ren, L., Yang, X., Bai, F., Wang, L., Geng, P., Bai, G., Shen, Y.(2011) J Struct Biol 174: 196-202
- PubMed: 21111049
- DOI: https://doi.org/10.1016/j.jsb.2010.11.020
- Primary Citation of Related Structures:
3OLD, 3OLE, 3OLG, 3OLI - PubMed Abstract:
Human pancreatic ¦Á-amylase (HPA) catalyzes the hydrolysis of ¦Á-d-(1,4) glycosidic linkages in starch and is one of the major therapeutic targets for type II diabetes. Several acarviostatins isolated from Streptomyces coelicoflavus var. nankaiensis previously showed more potent inhibition of HPA than acarbose, which has been successfully used in clinical therapy. However, the molecular mechanisms by which acarviostatins inhibit HPA remains elusive. Here we determined crystal structures of HPA in complexes with a series of acarviostatin inhibitors (I03, II03, III03, and IV03). Structural analyses showed that acarviostatin I03 undergoes a series of hydrolysis and condensation reactions in the HPA active site, similar to acarbose, while acarviostatins II03, III03, and IV03 likely undergo only hydrolysis reactions. On the basis of structural analysis combined with kinetic assays, we demonstrate that the final modified product with seven sugar rings is best suited for occupying the full active site and shows the most efficient inhibition of HPA. Our high resolution structures reported here identify first time an interaction between an inhibitor and subsite-4 of the HPA active site, which we show makes a significant contribution to the inhibitory effect. Our results provide important information for the design of new drugs for the treatment of type II diabetes or obesity.
Organizational Affiliation:
Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
