Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase

doi:10.1371/journal.pone.0036660

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 药物发现与设计中心

	Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase
	Jiang, Junfeng 1,2; Lu, Junyan 2; Lu, Dan 1; Liang, Zhongjie 1; Li, Lianchun 1; Ouyang, Sisheng 1; Kong, Xiangqian 1; Jiang, Hualiang2 ; Shen, Bairong 1; Luo, Cheng1,2
刊名	PLOS ONE
	2012-05-04
卷号	7 期号:5
ISSN号	1932-6203
DOI	10.1371/journal.pone.0036660
文献子类	Article
英文摘要	The histone acetylation of post-translational modification can be highly dynamic and play a crucial role in regulating cellular proliferation, survival, differentiation and motility. Of the enzymes that mediate post-translation modifications, the GCN5 of the histone acetyltransferase (HAT) proteins family that add acetyl groups to target lysine residues within histones, has been most extensively studied. According to the mechanism studies of GCN5 related proteins, two key processes, deprotonation and acetylation, must be involved. However, as a fundamental issue, the structure of hGCN5/AcCoA/pH3 remains elusive. Although biological experiments have proved that GCN5 mediates the acetylation process through the sequential mechanism pathway, a dynamic view of the catalytic process and the molecular basis for hGCN5/AcCoA/pH3 are still not available and none of theoretical studies has been reported to other related enzymes in HAT family. To explore the molecular basis for the catalytic mechanism, computational approaches including molecular modeling, molecular dynamic (MD) simulation and quantum mechanics/molecular mechanics (QM/MM) simulation were carried out. The initial hGCN5/AcCoA/pH3 complex structure was modeled and a reasonable snapshot was extracted from the trajectory of a 20 ns MD simulation, with considering post-MD analysis and reported experimental results. Those residues playing crucial roles in binding affinity and acetylation reaction were comprehensively investigated. It demonstrated Glu80 acted as the general base for deprotonation of Lys171 from H3. Furthermore, the two-dimensional QM/MM potential energy surface was employed to study the sequential pathway acetylation mechanism. Energy barriers of addition-elimination reaction in acetylation obtained from QM/MM calculation indicated the point of the intermediate ternary complex. Our study may provide insights into the detailed mechanism for acetylation reaction of GCN5, and has important implications for the discovery of regulators against GCN5 enzymes and related HAT family enzymes.
资助项目	State Key Program of Basic Research of China[2009CB918502] ; National Natural Science Foundation of China[20972174] ; National Natural Science Foundation of China[21021063] ; National Natural Science Foundation of China[20872107] ; National Natural Science Foundation of China[91029703] ; National Natural Science Foundation of China[91029704] ; Shanghai Committee of Science and Technology[10410703900] ; Chinese Academy of Sciences[XDA01040305]
WOS关键词	CATALYTIC MECHANISM ; CRYSTAL-STRUCTURE ; COENZYME-A ; PROTON-WIRE ; TRANSCRIPTIONAL COACTIVATOR ; N-ACETYLTRANSFERASES ; POSITIVE REGULATION ; MOLECULAR-DYNAMICS ; KINETIC MECHANISM ; GENE-EXPRESSION
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	PUBLIC LIBRARY SCIENCE
WOS记录号	WOS:000305349800106
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278080]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Jiang, Junfeng
作者单位	1.Soochow Univ, Ctr Syst Biol, Suzhou, Jiangsu, Peoples R China; 2.Chinese Acad Med Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Jiang, Junfeng,Lu, Junyan,Lu, Dan,et al. Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase[J]. PLOS ONE,2012,7(5).
APA	Jiang, Junfeng.,Lu, Junyan.,Lu, Dan.,Liang, Zhongjie.,Li, Lianchun.,...&Luo, Cheng.(2012).Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase.PLOS ONE,7(5).
MLA	Jiang, Junfeng,et al."Investigation of the Acetylation Mechanism by GCN5 Histone Acetyltransferase".PLOS ONE 7.5(2012).