Inhibition mechanism of cathepsin L-specific inhibitors based on the crystal structure of papain-CLIK148 complex

Papain was used as an experimental model structure to understand the inhibi tion mechanism of newly developed specific inhibitors of cathepsin L, the p apain superfamily. Recently, we developed a series of cathepsin L-specific inhibitors which are called the CLIK series [(1999) FEBS Lett. 458, 6-10]. Here, we report the complex structure of papain with CLIK148, which is a re presentative inhibitor from the CLIK series. The inhibitor complex structur e was solved at 1.7 ii resolution with conventional R 0.177. Unlike other e poxisuccinate inhibitors (E64, CA030, and CA074), CLIK148 uses both prime a nd nonprime sites, which are important for the specific inhibitory effect o n cathepsin L. Also, the specificity for cathepsin L could be explained by the existence of Phe in the P2 site and hydrophobic interaction of N-termin al pyridine ring. (C) 1999 Academic Press.