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3OLD

Crystal structure of alpha-amylase in complex with acarviostatin I03

Summary for 3OLD
Entry DOI10.2210/pdb3old/pdb
Related3OLE 3OLG
Related PRD IDPRD_900001 PRD_900009 PRD_900065
DescriptorPancreatic alpha-amylase, 6-AMINO-4-HYDROXYMETHYL-CYCLOHEX-4-ENE-1,2,3-TRIOL, PYROGLUTAMIC ACID, ... (13 entities in total)
Functional Keywordsglycosylation, hydrolase-hydrolase inhibitor complex, acarviostatin i03, hydrolase/hydrolase inhibitor
Biological sourceHomo sapiens (human)
Cellular locationSecreted, extracellular space: P04746
Total number of polymer chains1
Total formula weight58635.29
Authors
Qin, X.,Ren, L. (deposition date: 2010-08-26, release date: 2011-04-13, Last modification date: 2023-11-01)
Primary citationQin, 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: 21111049
DOI: 10.1016/j.jsb.2010.11.020
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (2 Å)
Structure validation

227561

數據於2024-11-20公開中

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