Sharma Vidhu, Panwar Preety, O'Donoghue Anthony J, Cui Haoran, Guido Rafael V C, Craik Charles S, Brömme Dieter
*Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC, Canada V6T1Z3.
†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.
Biochem J. 2015 Jan 1;465(1):163-73. doi: 10.1042/BJ20140809.
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.
人组织蛋白酶K（CatK）是治疗骨质疏松症的主要药物靶点。尽管其胶原酶活性独特，但CatK还具有强大的弹性蛋白酶活性，这一活性与人组织蛋白酶V和S相同。结构相似的半胱氨酸组织蛋白酶家族的其他成员，并不表现出显著的胶原蛋白和弹性蛋白降解活性。这就引出了这些活性是否需要特定结构元件（外部位点）存在的问题。CatK有两个控制其胶原酶活性和弹性蛋白酶活性的外部位点。对外部位点1和2的修饰会阻断CatK的弹性蛋白酶活性，而只有外部位点1的改变会阻止胶原分解。两个外部位点均不影响CatK的催化活性、蛋白酶稳定性、亚位点特异性或该蛋白酶对其他生物底物 的降解。一种与外部位点1结合的低分子量抑制剂可抑制CatK的弹性蛋白酶和胶原酶活性，而不会干扰其他蛋白质底物的降解。CatK外部位点的鉴定为设计高效抑制剂开辟了前景，这些抑制剂可选择性抑制这种多功能蛋白酶对治疗相关底物的降解。
