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Cystatin inhibition of cathepsin B requires dislocation of the proteinase occluding loop. Demonstration by release of loop anchoring through mutation of His110
Author(s) -
Pavlova Alla,
Krupa Joanne C,
Mort John S,
Abrahamson Magnus,
Björk Ingemar
Publication year - 2000
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(00)02337-1
Subject(s) - cathepsin b , cathepsin o , cathepsin c , cystatin , chemistry , loop (graph theory) , cathepsin a , cystatin c , mutation , cathepsin l , cathepsin h , enzyme , cathepsin , cathepsin s , biochemistry , biophysics , biology , gene , mathematics , combinatorics , renal function
Cystatins A and C were both shown to inhibit cathepsin B by a two‐step mechanism, involving an initial weak interaction followed by a conformational change. Disruption of the major salt bridge anchoring the occluding loop of cathepsin B to the main body of the enzyme by mutation of His110 to Ala converted the binding to an apparent one‐step reaction. The second step of cystatin binding to cathepsin B must therefore be due to the inhibitor having to alter the conformation of the enzyme by displacing the occluding loop to allow a tight complex to be formed. Cystatin A was appreciably less effective in displacing the loop than cystatin C, resulting in a considerably lower overall inhibition rate constant.