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题名: Two TPX2-Dependent Switches Control the Activity of Aurora A
作者: Xu, Xue1;  Wang, Xia1;  Xiao, Zhengtao1;  Li, Yan2, 3;  Wang, Yonghua1
刊名: PLOS ONE
发表日期: 2011-02-09
DOI: 10.1371/journal.pone.0016757
卷: 6, 期:2
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
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.
关键词[WOS]: AMBER FORCE-FIELD ;  DYNAMICS SIMULATION ;  MOLECULAR-DYNAMICS ;  A ACTIVATION ;  KINASE ;  PROTEIN ;  CANCER ;  TPX2 ;  CRYSTALLOGRAPHY ;  CENTROSOME
语种: 英语
WOS记录号: WOS:000287361700032
Citation statistics: 
内容类型: 期刊论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/142491
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.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

Recommended Citation:
Xu, Xue,Wang, Xia,Xiao, Zhengtao,et al. Two TPX2-Dependent Switches Control the Activity of Aurora A[J]. PLOS ONE,2011,6(2).
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