An allosteric site enables fine-tuning of cathepsin K by diverse effectors

FEBS Lett. 2016 Dec;590(24):4507-4518. doi: 10.1002/1873-3468.12495. Epub 2016 Nov 26.

Abstract

The cysteine peptidase cathepsin K is a potent collagenolytic enzyme and a promising target for the treatment of osteoporosis. Here, we characterize its allosteric fine-tuning via a recently identified allosteric site. We show that compound NSC94914 binds this site and acts as a specific partial inhibitor of the collagenolytic activity of cathepsin K. We link the functional differences between NSC94914 and known effectors (compound NSC11345 and glycosaminoglycans) to their different modes of interaction with the site. We characterize the allosteric site by site-directed mutagenesis and show that it is involved in specific regulation of the collagenolytic activity of cathepsin K.

Keywords: allostery; collagenase; cysteine protease; inhibitor.

Publication types

  • Letter

MeSH terms

  • Allosteric Regulation
  • Allosteric Site
  • Benzoates / chemistry*
  • Cathepsin K / antagonists & inhibitors
  • Cathepsin K / chemistry*
  • Cathepsin K / genetics
  • Cathepsin K / metabolism
  • Collagen / chemistry
  • Collagen / metabolism
  • Crystallography, X-Ray
  • Elastin / chemistry
  • Elastin / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Gene Expression
  • Glycosaminoglycans / chemistry*
  • Humans
  • Hydrolysis
  • Kinetics
  • Methylmalonic Acid / analogs & derivatives*
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Mutation
  • Protease Inhibitors / chemistry*
  • Protein Domains
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship
  • Substrate Specificity

Substances

  • Benzoates
  • Glycosaminoglycans
  • NSC13345
  • Protease Inhibitors
  • Recombinant Proteins
  • Methylmalonic Acid
  • Collagen
  • Elastin
  • Cathepsin K