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论文类型：期刊论文

发表时间：2011-02-09

发表刊物：PLOS ONE

收录刊物：Scopus、SCIE

卷号：6

期号：2

ISSN号：1932-6203

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.