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题名: Role of Bivalent Cations in Structural Stabilities of New Drug Targets-Vaccinia-related Kinases (VRK) from Molecular Dynamics Simulations
作者: Fu, Ting1, 2, 3;  Ren, Hong4;  Zhang, Jiajing4;  Ren, Pengyu4, 5;  Enyedy, Istvan6;  Li, Guohui1
关键词: Pseudokinases ;  vaccinia related kinase ;  bivalent cations ;  structural stabilities ;  molecular dynamics simulations
刊名: CURRENT PHARMACEUTICAL DESIGN
发表日期: 2013-04-01
卷: 19, 期:12, 页:2269-2281
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology ;  Life Sciences & Biomedicine
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
英文摘要: Protein kinases, which play an important role in the regulation of the majority of cellular processes, especially those involved in cellular signal transduction, by catalyzing the phosphorylation of specific proteins, are the attractive targets of drug design in pharmaceuticals industry. Interestingly, up to 10% of proteins in the human kinome termed pseudokinases are predicted to be enzymatically inactive, but are still pivotal in regulating diverse cellular processes and thus may be a potential therapeutic target to a certain extent. To study the underlying molecular mechanisms, molecular dynamics simulations were performed to investigate the role of bivalent cations Mg2+ and Mn2+ in the structural stabilities and dynamical behaviors of vaccinia related kinase 3 (VRK3), which was the first solved crystal structure of the pseudokinase, and that of its closest active relatives VRK1 and VRK2. Toward this end, a series of molecular dynamics simulations have been performed with different divalent cations binding modes in the active site. The simulations suggested that the binding of Mg2+ in the active site played a key structural role in the stabilization of VRK1 and VRK2, and Mn2+ was slightly required for VRK2. By contrast, the pseudokinase VRK3 was well ordered with lower RMSD values indicating it was rigid and very stable regardless of whether the bivalent cations were bound or not during the simulations. The present study provided evidence for the role of bivalent cations in structural stabilities of VRKs and the proposed simulation model reconciled the interpretation of available experimental structural and thermal denaturation assay data. These results gave us further information on the dynamical behaviors of the active site of VRKs and suggested a mechanism of regulation of their structural stabilities, and might provide a starting point for the more detailed follow-up investigation of drug design.
关键词[WOS]: PROTEIN-KINASE ;  SUPERFAMILY ;  ACTIVATION ;  REVEALS ;  BINDING ;  FAMILY
语种: 英语
WOS记录号: WOS:000316457700014
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/137639
Appears in Collections:中国科学院大连化学物理研究所_期刊论文

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作者单位: 1.Chinese Acad Sci, Dalian Inst Chem Phys, State key Lab Mol React Dynam, Lab Mol Modeling & Design, Dalian 116023, Peoples R China
2.Chinese Acad Sci, Grad Univ, Beijing 100049, Peoples R China
3.Dalian Univ Technol, Sch Life Sci & Biotechnol, Dalian 116024, Peoples R China
4.Shandong Univ, Sch Med, Qi Lu Hosp, Dept Ophthalmol, Jinan 250012, Peoples R China
5.Univ Texas Austin, Dept Biomed Engn, Austin, TX 78712 USA
6.Biogen Idec Inc, Cambridge, MA 02142 USA

Recommended Citation:
Fu, Ting,Ren, Hong,Zhang, Jiajing,et al. Role of Bivalent Cations in Structural Stabilities of New Drug Targets-Vaccinia-related Kinases (VRK) from Molecular Dynamics Simulations[J]. CURRENT PHARMACEUTICAL DESIGN,2013,19(12):2269-2281.
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