胶原酶
组织蛋白酶
化学
弹性蛋白酶
生物化学
组织蛋白酶K
弹性蛋白
组织蛋白酶G
蛋白酶
丝氨酸蛋白酶
蛋白质水解
蛋白酵素
酶
生物
体外
破骨细胞
遗传学
作者
Vidhu Sharma,Pankaj Panwar,Anthony J. O’Donoghue,Hongyuan Cui,Rafael Victório Carvalho Güido,Charles S. Craik,Dieter Brömme
摘要
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.
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