Catalytic Mechanism of Histone Acetyltransferase p300: From the Proton Transfer to Acetylation Reaction
文献类型：期刊论文
| 作者 | Zhang, Xinlei2,3; Ouyang, Sisheng3; Kong, Xiangqian3; Liang, Zhongjie5; Lu, Junyan3; Zhu, Kongkai3; Zhao, Dan3; Zheng, Mingyue3 ; Jiang, Hualiang3; Liu, Xin4
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| 刊名 | JOURNAL OF PHYSICAL CHEMISTRY B
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| 出版日期 | 2014-02-27 |
| 卷号 | 118期号:8页码:2009-2019 |
| ISSN号 | 1520-6106 |
| DOI | 10.1021/jp409778e |
| 文献子类 | Article |
| 英文摘要 | The transcriptional coactivator and histone acetyl-transferase (HAT) p300 acetylates the four core histones and other transcription factors to regulate a plethora of fundamental biological processes including cell growth, development, oncogenesis and apoptosis. Recent structural and biochemical studies on the p300 HAT domain revealed a Theorell-Chance, or "hit-and-run", catalytic mechanism. Nonetheless, the chemical mechanism of the entire reaction process including the proton transfer (PT) scheme and consequent acetylation reaction route remains unclear. In this study, a combined computational strategy consisting of molecular modeling, molecular dynamic (MD) simulation, and quantum mechanics/molecular mechanics (QM/MM) simulation was applied to elucidate these important issues. An initial p300/H3/Ac-CoA complex structure was modeled and optimized using a 100 ns MD simulation. Residues that play important roles in substrate binding and the acetylation reaction were comprehensively investigated. For the first time, these studies reveal a plausible PT scheme consisting of Y1394, D1507, and a conserved crystallographic water molecule, with all components of the scheme being stable during the MD simulation and the energy barrier low for PT to occur. The two-dimensional potential energy surface for the nucleophilic attack process was also calculated. The comparison of potential energies for two possible elimination half-reaction mechanisms revealed that Y1467 reprotonates the coenzyme-A leaving group to form product. This study provides new insights into the detailed catalytic mechanism of p300 and has important implications for the discovery of novel small molecule regulators for p300. |
| WOS关键词 | GCN5 TRANSCRIPTIONAL COACTIVATOR ; ARYLAMINE N-ACETYLTRANSFERASE-2 ; MOLECULAR-DYNAMICS ; ACYLATION REACTION ; STRUCTURAL BASIS ; EPIGENETIC CODE ; GENERAL BASE ; LYSINE 56 ; IDENTIFICATION ; BINDING |
| 资助项目 | Hi-Tech Research and Development Program of China[2012AA020302] ; National Natural Science Foundation of China[81230076] ; National Natural Science Foundation of China[91229204] ; National Natural Science Foundation of China[91029704] ; National Natural Science Foundation of China[21210003] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2013ZX09507-004] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2013ZX09507001] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program"[2014ZX09507002-005-012] ; National Institutes of Health[R01 GM060293] |
| WOS研究方向 | Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000332188300006 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277179]  |
| 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 | Luo, Cheng |
| 作者单位 | 1.Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA; 2.Fourth Mil Med Univ, Sch Pharm, Dept Med Chem & Pharmaceut Anal, Xian 710032, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.UT Southwest Med Ctr, Cecil H & Ida Green Ctr Reprod Biol Sci, Dallas, TX 75390 USA; 5.Soochow Univ, Ctr Syst Biol, Suzhou 215006, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Xinlei,Ouyang, Sisheng,Kong, Xiangqian,et al. Catalytic Mechanism of Histone Acetyltransferase p300: From the Proton Transfer to Acetylation Reaction[J]. JOURNAL OF PHYSICAL CHEMISTRY B,2014,118(8):2009-2019. |
| APA | Zhang, Xinlei.,Ouyang, Sisheng.,Kong, Xiangqian.,Liang, Zhongjie.,Lu, Junyan.,...&Luo, Cheng.(2014).Catalytic Mechanism of Histone Acetyltransferase p300: From the Proton Transfer to Acetylation Reaction.JOURNAL OF PHYSICAL CHEMISTRY B,118(8),2009-2019. |
| MLA | Zhang, Xinlei,et al."Catalytic Mechanism of Histone Acetyltransferase p300: From the Proton Transfer to Acetylation Reaction".JOURNAL OF PHYSICAL CHEMISTRY B 118.8(2014):2009-2019. |
入库方式： OAI收割
来源：上海药物研究所
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