Exploring the Conformational Landscape and Stability of Aurora A Using Ion-Mobility Mass Spectrometry and Molecular Modeling.
Exploring the Conformational Landscape and Stability of Aurora A Using Ion-Mobility Mass Spectrometry and Molecular Modeling.
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DOI：
10.1021/jasms.1c00271
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发表时间：
2022-03-02
影响因子：
3.2
通讯作者：
Eyers, Claire E.
中科院分区：
文献类型：
--
作者：
Tomlinson, Lauren J.;Batchelor, Matthew;Sarsby, Joscelyn;Byrne, Dominic P.;Brownridge, Philip J.;Bayliss, Richard;Eyers, Patrick A.;Eyers, Claire E.
蛋白激酶抑制剂在治疗由异常激酶信号驱动的疾病方面非常有效，并作为化学工具帮助解剖激酶信号复合物的细胞作用。评估小分子抑制剂结合对激酶构象动力学的影响有助于理解抑制和抗性机制。利用气相离子迁移质谱（IM-MS），研究人员表征了生理激活剂TPX2结合或小分子抑制作用驱动的蛋白激酶Aurora A （Aur A）构象和稳定性的变化。在分子模型的帮助下，我们建立了三个主要的构象，它们的相对丰度取决于Aur A的激活状态：一个高度密集的紧凑构象与大多数晶体结构相似，第二个高度密集的构象具有更开放的结构，在晶体结构中很少发现，另外一个低丰度的构象目前没有在蛋白质数据库中表示。值得注意的是，抑制剂结合诱导了未结合酶所采用的更紧凑的Aur A结构，IM-MS和模型都揭示了抑制剂介导的活性Aur A的稳定。
Protein kinase inhibitors are highly effective in treating diseases driven by aberrant kinase signaling and as chemical tools to help dissect the cellular roles of kinase signaling complexes. Evaluating the effects of binding of small molecule inhibitors on kinase conformational dynamics can assist in understanding both inhibition and resistance mechanisms. Using gas-phase ion-mobility mass spectrometry (IM-MS), we characterize changes in the conformational landscape and stability of the protein kinase Aurora A (Aur A) driven by binding of the physiological activator TPX2 or small molecule inhibition. Aided by molecular modeling, we establish three major conformations, the relative abundances of which were dependent on the Aur A activation status: one highly populated compact conformer similar to that observed in most crystal structures, a second highly populated conformer possessing a more open structure infrequently found in crystal structures, and an additional low-abundance conformer not currently represented in the protein databank. Notably, inhibitor binding induces more compact configurations of Aur A, as adopted by the unbound enzyme, with both IM-MS and modeling revealing inhibitor-mediated stabilization of active Aur A.
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DOI：
10.1042/bcj20180266
发表时间：
2018-08-14
期刊：
The Biochemical journal
影响因子：
--
作者：
Byrne DP;Li Y;Ngamlert P;Ramakrishnan K;Eyers CE;Wells C;Drewry DH;Zuercher WJ;Berry NG;Fernig DG;Eyers PA
通讯作者：
Eyers PA
影响因子：
5.8
作者：
Burgess SG;Oleksy A;Cavazza T;Richards MW;Vernos I;Matthews D;Bayliss R
通讯作者：
Bayliss R
DOI：
10.1083/jcb.201606077
发表时间：
2017-11-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bury L;Coelho PA;Simeone A;Ferries S;Eyers CE;Eyers PA;Zernicka-Goetz M;Glover DM
通讯作者：
Glover DM
影响因子：
4.7
作者：
Bavetsias V;Linardopoulos S
通讯作者：
Linardopoulos S
影响因子：
15
作者：
Deng, Lu;Broom, Aron;Klassen, John S.
通讯作者：
Klassen, John S.