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

• Published in: BIOPOLYM Vol. 51; no. 1; pp. 99 - 107
• Main Authors: Matsumoto, Keita, Mizoue, Kazutoshi, Kitamura, Kunihiro, Tse, Wai-Ching, Huber, Carol P., Ishida, Toshimasa
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 1999
• Subjects: actinidin; binding mode; Binding Sites; cathepsin B; cathepsin K; cathepsin L; Crystal structure; Crystallography, X-Ray; Cysteine Endopeptidases - chemistry; Cysteine Endopeptidases - metabolism; cysteine protease; Cysteine Proteinase Inhibitors - chemical synthesis; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Drug Design; E-64; E-64 derivative; Epoxy Compounds; inhibitory mechanism; Leucine - analogs & derivatives; Leucine - chemical synthesis; Leucine - chemistry; Leucine - pharmacology; Models, Molecular; Molecular dynamics; Molecular structure; papain; Protein Conformation; Static Electricity; Structure-Activity Relationship; Succinic Acid
• ISSN: 0006-3525; 1097-0282
• DOI: 10.1002/(SICI)1097-0282(1999)51:1<99::AID-BIP11>3.0.CO;2-R

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 Sn subsites of cysteine proteases. Although the Sn–Pn (n = 1 ∼ 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 S2–P2 and S3–P3 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. In contrast with similar binding/inhibitory modes of E‐64‐c and E‐64 for cysteine proteases, the inhibitory mechanism of cathepsin B‐specific CA074 results from the binding to the Sn′ subsite. © 1999 John Wiley & Sons, Inc. Biopoly 51: 99–107, 1999