The crystal structure of human cathepsin L complexed with E-64

We have determined the three dimensional structure of the complex of human cathepsin L and E64, an irreversible inhibitor of cysteine proteases, at 2.5 Angstrom resolution. The overall structure was similar to that of other known cysteine proteases and apparently identical to the mature region of procathepsin L. The electron density for E-64 is clearly visible except for the guanidinobutane moiety, From comparison of the active sites of cathepsin L and B, we found the following: (1) The S' subsites of cathepsin L and B are totally different because of the 'occluding loop' lying on the end of the S' subsites of cathepsin B, (2) The S-2 pocket of cathepsin L is shallow and narrow compared to that of cathepsin B, (3) The S-3 subsites of the two enzymes are more similar than the other subsites, but cathepsin L may accommodate a more bulky group at this site. Knowledge of the active site structure of cathepsin L should be helpful for the structure-based design of potent and specific inhibitors which are of therapeutic importance. (C) 1997 Federation of European Biochemical Societies.