Role of Bivalent Cations in Structural Stabilities of New Drug Targets-Vaccinia-related Kinases (VRK) from Molecular Dynamics Simulations

	Role of Bivalent Cations in Structural Stabilities of New Drug Targets-Vaccinia-related Kinases (VRK) from Molecular Dynamics Simulations
	Fu, Ting 1,2,3; Ren, Hong 4; Zhang, Jiajing 4; Ren, Pengyu 4,5; Enyedy, Istvan 6; Li, Guohui 1
刊名	current pharmaceutical design
	2013-04-01
卷号	19 期号:12 页码:2269-2281
关键词	Pseudokinases vaccinia related kinase bivalent cations structural stabilities molecular dynamics simulations
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.
WOS标题词	science & technology ; life sciences & biomedicine
类目[WOS]	pharmacology & pharmacy
研究领域[WOS]	pharmacology & pharmacy
关键词[WOS]	protein-kinase ; superfamily ; activation ; reveals ; binding ; family
收录类别	SCI
语种	英语
WOS记录号	WOS:000316457700014
公开日期	2015-11-10
内容类型	期刊论文
源URL	[http://159.226.238.44/handle/321008/137639]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
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
推荐引用方式 GB/T 7714	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.
APA	Fu, Ting,Ren, Hong,Zhang, Jiajing,Ren, Pengyu,Enyedy, Istvan,&Li, Guohui.(2013).Role of Bivalent Cations in Structural Stabilities of New Drug Targets-Vaccinia-related Kinases (VRK) from Molecular Dynamics Simulations.current pharmaceutical design,19(12),2269-2281.
MLA	Fu, Ting,et al."Role of Bivalent Cations in Structural Stabilities of New Drug Targets-Vaccinia-related Kinases (VRK) from Molecular Dynamics Simulations".current pharmaceutical design 19.12(2013):2269-2281.