Two TPX2-Dependent Switches Control the Activity of Aurora A

	Two TPX2-Dependent Switches Control the Activity of Aurora A
	Xu, Xue 1; Wang, Xia 1; Xiao, Zhengtao 1; Li, Yan 2,3; Wang, Yonghua 1
刊名	plos one
	2011-02-09
卷号	6 期号:2
英文摘要	aurora a is an important oncogenic kinase for mitotic spindle assembly and a potentially attractive target for human cancers. its activation could be regulated by atp cycle and its activator tpx2. to understand the activation mechanism of aurora a, a series of 20 ns molecular dynamics (md) simulations were performed on both the wild-type kinase and its mutants. analyzing the three dynamic trajectories (aurora a-atp, aurora a-adp, and aurora a-adp-tpx2) at the residue level, for the first time we find two tpx2-dependent switches, i.e., switch-1 (lys-143) and switch-2 (arg-180), which are tightly associated with aurora a activation. in the absence of tpx2, lys-143 exhibits a "closed'' state, and becomes hydrogen-bonded to adp. once tpx2 binding occurs, switch-1 is forced to "open'' the binding site, thus pulling adp away from aurora a. without facilitation of tpx2, switch-2 exits in an "open'' conformation which accompanies the outward-flipping movement of p.thr288 (in an inactive conformation), leading to the crucial phosphothreonine exposed and accessible for deactivation. however, with the binding of tpx2, switch-2 is forced to undergo a "closed'' movement, thus capturing p.thr288 into a buried position and locking its active conformation. analysis of two aurora a (k143a and r180a) mutants for the two switches further verifies their functionality and reliability in controlling aurora activity. our systems therefore suggest two switches determining aurora a activation, which are important for the development of aurora kinase inhibitors.
WOS标题词	science & technology
类目[WOS]	multidisciplinary sciences
研究领域[WOS]	science & technology - other topics
关键词[WOS]	amber force-field ; dynamics simulation ; molecular-dynamics ; a activation ; kinase ; protein ; cancer ; tpx2 ; crystallography ; centrosome
收录类别	SCI
语种	英语
WOS记录号	WOS:000287361700032
公开日期	2015-11-17
内容类型	期刊论文
源URL	[http://159.226.238.44/handle/321008/142491]
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.NW A&F Univ, Ctr Bioinformat, Yangling, Peoples R China 2.Dalian Univ Technol, Sch Chem Engn, Dalian, Peoples R China 3.Chinese Acad Sci, Dalian Inst Chem Phys, Lab Pharmaceut Resource Discovery, Dalian, Peoples R China
推荐引用方式 GB/T 7714	Xu, Xue,Wang, Xia,Xiao, Zhengtao,et al. Two TPX2-Dependent Switches Control the Activity of Aurora A[J]. plos one,2011,6(2).
APA	Xu, Xue,Wang, Xia,Xiao, Zhengtao,Li, Yan,&Wang, Yonghua.(2011).Two TPX2-Dependent Switches Control the Activity of Aurora A.plos one,6(2).
MLA	Xu, Xue,et al."Two TPX2-Dependent Switches Control the Activity of Aurora A".plos one 6.2(2011).