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 E-64, an irreversible inhibitor of cysteine proteases, at 2.5 A 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 S2 pocket of cathepsin L is shallow and narrow compared to that of cathepsin B. (3) The S3 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.
Fujishima
A
A
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Yodogawa-ku, Osaka, Japan. fujishim@lab.takeda.co.jp
Imai
Y
Y
Nomura
T
T
Fujisawa
Y
Y
Yamamoto
Y
Y
Sugawara
T
T
D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000235:genetics; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry*; D010450:Endopeptidases; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D011994:Recombinant Proteins / Q000737:chemistry
D015853:Cysteine Proteinase Inhibitors; D011994:Recombinant Proteins; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; C534281:CTSL protein, human; D056668:Cathepsin L; D007930:Leucine; C024974:E 64