title: Structural requirements for the collagenase and elastase activity of cathepsin K and its selective inhibition by an exosite inhibitor.
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.
authors.affiliation: *Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
authors.forename: Vidhu
authors.initials: V
authors.lastname: Sharma
authors.affiliation: *Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
authors.forename: Preety
authors.initials: P
authors.lastname: Panwar
authors.affiliation: †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.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: O'Donoghue
authors.affiliation: *Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
authors.forename: Haoran
authors.initials: H
authors.lastname: Cui
authors.affiliation: ‡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.
authors.forename: Rafael V C
authors.initials: RV
authors.lastname: Guido
authors.affiliation: †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.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Craik
authors.affiliation: *Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
authors.forename: Dieter
authors.initials: D
authors.lastname: Brömme
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D002417:Cattle; D003094:Collagen / Q000378:metabolism; D017364:Collagenases / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013329:Structure-Activity Relationship; D013379:Substrate Specificity / Q000187:drug effects
chemical_list: D050505:Mutant Proteins; D011480:Protease Inhibitors; D003094:Collagen; D010196:Pancreatic Elastase; D056657:Cathepsin K; D017364:Collagenases