An allosteric site enables fine-tuning of cathepsin K by diverse effectors

被引：15
作者：
Novinec, Marko [1 ]
Rebernik, Mateja [1 ]
Lenarcic, Brigita [1 ,2 ]
机构：
[1] Univ Ljubljana, Dept Chem & Biochem, Fac Chem & Chem Technol, Vecna Pot 113, SI-1000 Ljubljana, Slovenia
[2] Jozef Stefan Inst, Dept Biochem & Mol & Struct Biol, Ljubljana, Slovenia
来源：
FEBS LETTERS | 2016年 / 590卷 / 24期
关键词：
allostery; collagenase; cysteine protease; inhibitor; SELECTIVE-INHIBITION; COLLAGENASE; SYSTEM; ODANACATIB; MECHANISM; DISCOVERY; DISEASE; TERM;
D O I：
10.1002/1873-3468.12495
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
引用
收藏
页码：4507 / 4518
页数：12
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