Structural basis of inhibition of cysteine proteases by E-64 and its derivatives

✍ Scribed by Keita Matsumoto; Kazutoshi Mizoue; Kunihiro Kitamura; Wai-Ching Tse; Carol P. Huber; Toshimasa Ishida

• Publisher: Wiley (John Wiley & Sons)
• Year: 1999
• Tongue: English
• Weight: 466 KB
• Volume: 51
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/(sici)1097-0282(1999)51:1<99::aid-bip11>3.0.co;2-r

✦ Synopsis

This paper focuses on the inhibitory mechanism of E-64 and its derivatives (epoxysuccinyl-based inhibitors) with some cysteine proteases, based on the binding modes observed in the x-ray crystal structures of their enzyme-inhibitor complexes. E-64 is a potent irreversible inhibitor against general cysteine proteases, and its binding modes with papain, actinidin, cathepsin L, and cathepsin K have been reviewed at the atomic level. E-64 interacts with the S n subsites of cysteine proteases. Although the S n -P n (n ϭ 1 ϳ 3) interactions of the inhibitor with the main chains of the active site residues are similar in respective complexes, the significant difference is observed in the side-chain interactions of S 2 -P 2 and S 3 -P 3 pairs because of different residues constituting the respective subsites. E-64-c and CA074 are representative derivatives developed from E-64 as a clinical usable and a cathepsin B-specific inhibitors, respectively.