Loop interactions and dynamics tune the enzymatic activity of the human histone deacetylase 8.
Loop interactions and dynamics tune the enzymatic activity of the human histone deacetylase 8.
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DOI：
10.1021/ja408184x
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发表时间：
2013-11-27
影响因子：
15
通讯作者：
Hansen DF
中科院分区：
文献类型：
--
作者：
Kunze MB;Wright DW;Werbeck ND;Kirkpatrick J;Coveney PV;Hansen DF
人类组蛋白去乙酰化酶8 （HDAC8）是基因调控中的关键水解酶，已被确定为治疗多种癌症的药物靶点。在此之前，HDAC8酶已经通过生化技术、x射线晶体学和计算方法进行了广泛的研究。这些调查已经产生了活性部位的详细信息，并证明了基底入口表面是高度动态的。然而，目前尚不清楚入口表面的动力学如何调节和影响HDAC8的催化活性。利用长时间尺度的全原子分子动力学模拟，我们发现了一种机制，即两个环的相互作用和动力学调节HDAC8功能重要残基的构型，从而影响酶的活性。随后，我们使用一种成熟的荧光活性测定法和一种无创实时进展测定法来研究这一假设，其中通过核磁共振波谱观察到p53肽的去乙酰化。我们的工作提供了对HDAC8动态环路网络的详细见解，并为一些实验观察提供了解释。
The human histone deacetylase 8 (HDAC8) is a key hydrolase in gene regulation and has been identified as a drug target for the treatment of several cancers. Previously the HDAC8 enzyme has been extensively studied using biochemical techniques, X-ray crystallography, and computational methods. Those investigations have yielded detailed information about the active site and have demonstrated that the substrate entrance surface is highly dynamic. Yet it has remained unclear how the dynamics of the entrance surface tune and influence the catalytic activity of HDAC8. Using long time scale all atom molecular dynamics simulations we have found a mechanism whereby the interactions and dynamics of two loops tune the configuration of functionally important residues of HDAC8 and could therefore influence the activity of the enzyme. We subsequently investigated this hypothesis using a well-established fluorescence activity assay and a noninvasive real-time progression assay, where deacetylation of a p53 based peptide was observed by nuclear magnetic resonance spectroscopy. Our work delivers detailed insight into the dynamic loop network of HDAC8 and provides an explanation for a number of experimental observations.
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影响因子：
5.5
作者：
Hess, Berk;Kutzner, Carsten;Lindahl, Erik
通讯作者：
Lindahl, Erik
影响因子：
64.8
作者：
Bouvignies, Guillaume;Vallurupalli, Pramodh;Hansen, D. Flemming;Correia, Bruno E.;Lange, Oliver;Bah, Alaji;Vernon, Robert M.;Dahlquist, Frederick W.;Baker, David;Kay, Lewis E.
通讯作者：
Kay, Lewis E.
影响因子：
64.8
作者：
Lin, Yu-yi;Kiihl, Samara;Suhail, Yasir;Liu, Shang-Yun;Chou, Yi-hsuan;Kuang, Zheng;Lu, Jin-ying;Khor, Chin Ni;Lin, Chi-Long;Bader, Joel S.;Irizarry, Rafael;Boeke, Jef D.
通讯作者：
Boeke, Jef D.
影响因子：
2.7
作者：
Haider, Shozeb;Joseph, Caleb G.;Neidle, Stephen;Fierke, Carol A.;Fuchter, Matthew J.
通讯作者：
Fuchter, Matthew J.
DOI：
10.1002/prot.340230412
发表时间：
1995-12-01
期刊：
PROTEINS-STRUCTURE FUNCTION AND GENETICS
影响因子：
--
作者：
Frishman, D;Argos, P
通讯作者：
Argos, P