酪蛋白水解酶ClpP的结构研究与功能干预  

Structural research and functional intervention of Caseinolytic protease P

作　　者：王蓬宇 张涛 杨财广 Pengyu Wang;Tao Zhang;Cai-Guang Yang(School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,University of Chinese Academy of Sciences,Hangzhou 310024,China;State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Bohai Rim Advanced Research Institute for Drug Discovery,Yantai 264117,China)

机构地区：[1]国科大杭州高等研究院药物科学与技术学院,杭州310024 [2]中国科学院上海药物研究所新药研究国家重点实验室,上海201203 [3]中科环渤海(烟台)药物高等研究院,烟台264117

出　　处：《中国科学：化学》2024年第5期703-715,共13页SCIENTIA SINICA Chimica

基　　金：国家自然科学基金重点项目(编号:22037007);国家自然基金青年基金项目(编号:22107109);中国科学院青年创新促进会(编号:2023297)资助。

摘　　要：酪蛋白水解酶ClpP是一种高度保守的丝氨酸蛋白水解酶,通常与AAA+超家族ATP酶的伴侣蛋白形成复合物调控细胞内蛋白质稳态.化学干预ClpP蛋白水解酶的生物学功能,尤其是小分子激动剂的开发已被证明是治疗多种疾病的有效策略.近年来,本课题组围绕ClpP蛋白酶在结构生物学和化学生物学等研究领域取得了一些重要进展.一方面,通过结构生物学方法解析了金黄色葡萄球菌ClpP(SaClpP)不同状态下的三种构象的晶体结构;并发现SaClpP的功能激活型突变体,增加了对ClpP激动机制的理解.另一方面,针对病原菌和人线粒体ClpP开展小分子激动剂的化学干预研究,开发多类型骨架的ClpP小分子激动剂,实现对不同物种ClpP蛋白酶功能选择性激动,推动以ClpP为靶标的抗菌和抗肿瘤研究.Caseinolytic protease P(ClpP)is a highly conserved serine proteolytic enzyme,typically forming complexes with the AAA+superfamily ATPases as chaperone proteins to regulate protein homeostasis within cells.Chemical intervention of the biological function of ClpP protease,especially the development of small-molecule agonists on ClpP protease,has been demonstrated as effective strategies for the treatment of a variety of diseases.In recent years,our group has made significant progress on ClpP protease in structural biology and chemical biology.On one hand,we employed structural biology methods to elucidate the crystal structures of Staphylococcus aureus ClpP(SaClpP)in three different conformations.Additionally,a gain-of-function mutant of SaClpP has been identified,which enhanced the understanding of the mechanism on ClpP activation.On the other hand,our group has undertaken the research on chemical intervention of pathogenic bacteria and human mitochondrial ClpP by small molecule agonists.We have developed small-molecule ClpP agonists with diverse structural scaffolds,and achieved selective activation of ClpP protease function across different species.These advances have promoted the ClpP-targeted antibacterial and antitumor research.

关 键 词：酪蛋白水解酶ClpP 分子识别 化学干预 抗菌 抗肿瘤 

分 类 号：Q55[生物学—生物化学]