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

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Abstract
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