Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10822567 | Current Opinion in Structural Biology | 2013 | 9 Pages |
Abstract
β-Secretase (BACE1) is a membrane-anchored pepsin-like aspartic protease and is the rate-limiting enzyme in the β-amyloidogenic pathway. Thus, inhibitors of BACE1 activity have therapeutic potential for Alzheimer's disease. While much effort has focused on small molecule active site inhibitors, recent exploration of BACE1 inhibition by peptides and antibodies has revealed exosites that can regulate enzymatic activity. This type of allosteric regulation by proteinaceous factors, while frequently found in serine and cysteine proteases, is rarely seen in aspartic proteases. A crystal structure of the anti-BACE1/enzyme complex shows altered structural features and dynamic characteristics near the substrate-binding cleft. This binding mode, along with the enzymatic inhibition pattern, suggests that anti-BACE1 functions through an allosteric inhibition mechanism.
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Authors
Weiru Wang, Yichin Liu, Robert A Lazarus,