Structural requirements for cathepsin B and cathepsin H inhibition by kininogens.
Domain 3 (D3) of human kininogens, the major cysteine proteinase inhibitors in plasma, has been shown to be the tightest binding inhibitory domain for cathepsins B and H. D3 was expressed in three fragments as its exon products as follows: exon 7 (Gly235-Gln292), exon 8 (Gln292-Gly328), and exon 9 (Gln329-Met357). Exon products 7, 8, and 9 alone as well as exon product 7 + 9 each exhibited an 1C50 value 5- to 30-fold higher (5-30 microM) than exon products 7 + 8 and 8 + 9 (0.9-1.3 microM) for cathepsins B and H, respectively. However, in turn, the exon products 7 + 8 and 8 + 9 seemed to be less potent inhibitors than the intact D3 (10, 200 nM) or HK (200, 500 nM) molecule. These results clearly indicate that an intact molecule of HK or its domain 3 as a whole is required for optimal inhibition of cathepsins B and H.
Sol Sherry Thrombosis Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
B
B
Bano
S P
SP
Kunapuli
H N
HN
Bradford
R W
RW
Colman
D000595:Amino Acid Sequence; D002401:Cathepsin B / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D056655:Cathepsin H; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D003546:Cysteine Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007704:Kininogens / Q000494:pharmacology*; D008969:Molecular Sequence Data
D004791:Enzyme Inhibitors; D007704:Kininogens; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534126:CTSH protein, human; D056655:Cathepsin H