3OLD
Crystal structure of alpha-amylase in complex with acarviostatin I03
Summary for 3OLD
| Entry DOI | 10.2210/pdb3old/pdb |
| Related | 3OLE 3OLG |
| Related PRD ID | PRD_900001 PRD_900009 PRD_900065 |
| Descriptor | Pancreatic alpha-amylase, 6-AMINO-4-HYDROXYMETHYL-CYCLOHEX-4-ENE-1,2,3-TRIOL, PYROGLUTAMIC ACID, ... (13 entities in total) |
| Functional Keywords | glycosylation, hydrolase-hydrolase inhibitor complex, acarviostatin i03, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Secreted, extracellular space: P04746 |
| Total number of polymer chains | 1 |
| Total formula weight | 58635.29 |
| Authors | |
| Primary citation | Qin, X.,Ren, L.,Yang, X.,Bai, F.,Wang, L.,Geng, P.,Bai, G.,Shen, Y. Structures of human pancreatic alpha-amylase in complex with acarviostatins: Implications for drug design against type II diabetes J.Struct.Biol., 174:196-202, 2011 Cited by PubMed Abstract: Human pancreatic α-amylase (HPA) catalyzes the hydrolysis of α-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. PubMed: 21111049DOI: 10.1016/j.jsb.2010.11.020 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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