肝素硫酸盐可以选择性地抑制 cathepsin K 的原酶活性
Xiaoxiao Zhang1, Yin Luo1,2, Huanmeng Hao1,2
1Department of Oral Biology, School of Dental Medicine, University at Buffalo, the State University of New York, Buffalo, NY 14214, USA.
bioRxiv : the preprint server for biology
|January 23, 2024
概括
肝硫酸盐 (HS) 与甲素K (CtsK) 结合,形成二次体并抑制原酶活性. HS寡糖体显示出作为选择性CtsK抑制剂的潜力,用于骨再吸收疾病.
科学领域:
- 生物化学 生物化学
- 结构生物学 结构生物学
- 骨生物学 骨生物学 骨生物学
背景情况:
- 甲素K (CtsK) 是骨重塑中的一个关键的囊蛋白酶,由骨质细胞高度表达.
- 已知CtsK与肝素硫酸盐 (HS) 之间的相互作用,但其结构基础和功能后果尚不清楚.
研究的目的:
- 阐明CtsK-HS相互作用的结构基础.
- 为了确定HS如何调节CtsK的酶活性.
- 探索HS寡糖类作为潜在的治疗药物用于骨再吸收疾病.
主要方法:
- 橄糖化合物结合测定.
- 酶活性测定 (酶和原酶).
- CtsK-HS复合物的X射线晶体学.
- 位点定向的突变发生.
- 在体外的骨质再吸收试验.
主要成果:
- CtsK优先结合较大的HS寡糖类 (多德卡糖类,12mer),从而诱导二分化.
- HS以硫化依赖的方式抑制CtsK原酶活性,但保留了酶活性.
- 晶体结构显示HS与活性部位的远程结合,由六个基本残留物介导.
- 在实验室中,HS 12mers有效地抑制了骨质细胞骨的再吸收.
结论:
- 肝素硫酸盐作为Cathepsin K活动的多方面调节剂.
- 基于HS的寡糖体代表了一种潜在的新类选择性CtsK抑制剂,用于过度骨再吸收的疾病.
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