title: An allosteric site enables fine-tuning of cathepsin K by diverse effectors.
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.
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia.
authors.forename: Marko
authors.initials: M
authors.lastname: Novinec
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia.
authors.forename: Mateja
authors.initials: M
authors.lastname: Rebernik
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Slovenia.|Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia.
authors.forename: Brigita
authors.initials: B
authors.lastname: Lenarčič
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D001565:Benzoates / Q000737:chemistry*; D056657:Cathepsin K / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004549:Elastin / Q000737:chemistry / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006025:Glycosaminoglycans / Q000737:chemistry*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D008764:Methylmalonic Acid / Q000031:analogs & derivatives*; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011480:Protease Inhibitors / Q000737:chemistry*; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001565:Benzoates; D006025:Glycosaminoglycans; C000601669:NSC13345; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D008764:Methylmalonic Acid; D003094:Collagen; D004549:Elastin; D056657:Cathepsin K
keywords: allostery; collagenase; cysteine protease; inhibitor