Inhibition and Mechanism of HDAC8 Revisited

doi:10.1021/ja501548p

CORC > 北京大学 > 化学与分子工程学院

	Inhibition and Mechanism of HDAC8 Revisited
	Chen, Kai ; Zhang, Xiaoxiao ; Wu, Yun-Dong ; Wiest, Olaf
刊名	journal of the american chemical society
	2014
关键词	HISTONE DEACETYLASE INHIBITORS AB-INITIO QM/MM ZINC-BINDING GROUPS ACTIVE-SITE CATALYTIC-ACTIVITY CRYSTAL-STRUCTURE HYDROXAMIC ACIDS CANCER-THERAPY PROTEIN TSA
DOI	10.1021/ja501548p
英文摘要	Histone deacetylases (HDACs) have found intense interest as drug targets for a variety of diseases, but there is disagreement about basic aspects of the inhibition and mechanism of HDACs. QM/MM calculations of HDAC8 including a large QM region provide a model that is consistent with the available crystal structures and structure-activity relationships of different HDAC inhibitors. The calculations support a spontaneous proton transfer from a hydroxamic acid to an active site histidine upon binding to the zinc. The role of the H142/D176 catalytic dyad as the general base of the reaction is elucidated. The reasons for the disagreements between previous proposals are discussed. The results provide detailed insights into the unique mechanism of HDACs, including the role of the two catalytic dyads and function of the potassium near the active site. They also have important implications for the design of novel inhibitors for a number of HDACs such as the class IIa HDACs.; Chemistry, Multidisciplinary; SCI(E); EI; PubMed; 9; ARTICLE; owiest@nd.edu; 33; 11636-11643; 136
语种	英语
内容类型	期刊论文
源URL	[http://ir.pku.edu.cn/handle/20.500.11897/188869]
专题	化学与分子工程学院
推荐引用方式 GB/T 7714	Chen, Kai,Zhang, Xiaoxiao,Wu, Yun-Dong,et al. Inhibition and Mechanism of HDAC8 Revisited[J]. journal of the american chemical society,2014.
APA	Chen, Kai,Zhang, Xiaoxiao,Wu, Yun-Dong,&Wiest, Olaf.(2014).Inhibition and Mechanism of HDAC8 Revisited.journal of the american chemical society.
MLA	Chen, Kai,et al."Inhibition and Mechanism of HDAC8 Revisited".journal of the american chemical society (2014).