3OLE

Structures of human pancreatic alpha-amylase in complex with acarviostatin II03

3OLE の概要

• エントリーDOI: 10.2210/pdb3ole/pdb
• 関連するPDBエントリー: 3OLD 3OLG
• 関連するBIRD辞書のPRD_ID: PRD_900009 PRD_900065
• 分子名称: Pancreatic alpha-amylase, 6-AMINO-4-HYDROXYMETHYL-CYCLOHEX-4-ENE-1,2,3-TRIOL, PYROGLUTAMIC ACID, ... (13 entities in total)
• 機能のキーワード: glycosylation, hydrolase-hydrolase inhibitor complex, acarviostatin ii03, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Secreted, extracellular space: P04746
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 58794.47

構造登録者

Qin, X.,Ren, L. (登録日: 2010-08-26, 公開日: 2011-04-13, 最終更新日: 2023-11-01)

主引用文献

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

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

実験手法

X-RAY DIFFRACTION (1.55 Å)