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Biochem J. 2015 Jan 1;465(1):163-73. doi: 10.1042/BJ20140809.

Structural requirements for the collagenase and elastase activity of cathepsin K and its selective inhibition by an exosite inhibitor.

Author information

1
*Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
2
†Department of Pharmaceutical Chemistry, Program in Chemistry and Chemical Biology and Graduate Group in Biophysics, University of California at San Francisco, San Francisco, CA 94143, U.S.A.
3
‡Laboratório de Química Medicinal e Computacional, Centro de Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos-SP 13563-120, Brazil.

Abstract

Human cathepsin K (CatK) is a major drug target for the treatment of osteoporosis. Although its collagenase activity is unique, CatK also exerts a potent elastolytic activity that is shared with human cathepsins V and S. Other members of the cysteine cathepsin family, which are structurally similar, do not exhibit significant collagen and elastin degrading activities. This raises the question of the presence of specific structural elements, exosites, that are required for these activities. CatK has two exosites that control its collagenolytic and elastolytic activity. Modifications of exosites 1 and 2 block the elastase activity of CatK, whereas only exosite-1 alterations prevent collagenolysis. Neither exosite affects the catalytic activity, protease stability, subsite specificity of CatK or the degradation of other biological substrates by this protease. A low-molecular-mass inhibitor that docks into exosite-1 inhibits the elastase and collagenase activity of CatK without interfering with the degradation of other protein substrates. The identification of CatK exosites opens up the prospect of designing highly potent inhibitors that selectively inhibit the degradation of therapeutically relevant substrates by this multifunctional protease.

PMID:
25279554
DOI:
10.1042/BJ20140809
[Indexed for MEDLINE]

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