title: Probing the activity modification space of the cysteine peptidase cathepsin K with novel allosteric modifiers.
abstract: Targeting allosteric sites is gaining increasing recognition as a strategy for modulating the activity of enzymes, especially in drug design. Here we investigate the mechanisms of allosteric regulation of cathepsin K as a representative of cysteine cathepsins and a promising drug target for the treatment of osteoporosis. Eight novel modifiers are identified by computational targeting of predicted allosteric sites on the surface of the enzyme. All act via hyperbolic kinetic mechanisms in presence of low molecular mass substrates, as expected for allosteric effectors. Two compounds have sizable effects on enzyme activity using interstitial collagen as a natural substrate of cathepsin K and four compounds show a significantly stabilizing effect on cathepsin K. The concept of activity modification space is introduced to obtain a global perspective of the effects elicited by the modifiers. Analysis of the activity modification space reveals that the activity of cathepsin K is regulated via multiple, different allosteric mechanisms.
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia; Department of Biochemistry, University of Zürich, Zürich, Switzerland.
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, Ljubljana, Slovenia; Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia.
authors.forename: Brigita
authors.initials: B
authors.lastname: Lenarčič
authors.affiliation: Department of Biochemistry, University of Zürich, Zürich, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Baici
mesh_terms: D000494:Allosteric Regulation; D056657:Cathepsin K / Q000737:chemistry* / Q000378:metabolism; D004795:Enzyme Stability; D006801:Humans; D010024:Osteoporosis / Q000201:enzymology
chemical_list: C534130:CTSK protein, human; D056657:Cathepsin K