Structural insights and influence of V599 mutations on the overall dynamics of BRAF protein against its kinase domains,Integrative Biology

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Structural insights and influence of V599 mutations on the overall dynamics of BRAF protein against its kinase domains
Integrative Biology ( IF 1.5 ) Pub Date : 2018-09-19 , DOI: 10.1039/c8ib00095f
Mayank Mayank _{1,

2,

3} , Navneet Kaur _{1,

3,

4} , Narinder Singh _{1,

2,

3}

Affiliation

Mutations in the BRAF gene are well known for their oncogenic effects. Point mutations in V599 are particularly oncogenic and are considered important for therapeutic purposes. Along with wild type, other V599 mutated BRAF variants viz. V599E, V599D and V599R are reported and crystals of the former two with inhibitor (BAY43-9006) are further detailed. Both wild-type and mutated BRAF forms show similar interaction patterns with BAY43-9006, but the 599th residue did not show any involvement in the interactions. Upon BAY43-9006 binding, kinase domains of both forms were found adopting essentially identical conformations. However, BAY43-9006 shows a varied activity profile in the case of the wild and V599E variant of the BRAF protein. Furthermore, MMGBSA binding energy results for all four BRAF variants, further revealed the importance of the 599th residue. In-depth analysis viz. molecular dynamics, residue correlation studies and residue interaction network (RIN) analyses were conducted, providing a deep insight into the 599th residue and its impact on the overall dynamics of BRAF protein. Our findings reveal that the mutated residue at the 599th position not only changed the BAY43-9006–BRAF binding behaviour but also produced a massive impact on the overall dynamic behaviour of the protein. The insights obtained herein could be of great relevance for designing new BRAF inhibitors aimed at getting ideal activity against all BRAF forms.

中文翻译：

V599突变的结构见解及其对BRAF蛋白针对其激酶结构域的整体动力学的影响

众所周知，BRAF基因的突变具有致癌作用。V599中的点突变特别致癌，并被认为对治疗具有重要意义。与野生型一起，其他V599突变的BRAF变种也就是。报告了V599E，V599D和V599R，并进一步详细说明了前两种带抑制剂的晶体（BAY43-9006）。野生型和突变BRAF形式均显示与BAY43-9006相似的相互作用模式，但第599个残基未显示参与相互作用。在BAY43-9006结合后，发现两种形式的激酶结构域都采用基本相同的构象。但是，BAY43-9006在野生型和V599E变种的情况下显示出不同的活性谱。BRAF蛋白。此外，所有四个BRAF变体的MMGBSA结合能结果，进一步揭示了第599个残基的重要性。深入分析即。进行了分子动力学，残基相关性研究和残基相互作用网络（RIN）分析，从而深入了解了第599位残基及其对BRAF蛋白整体动力学的影响。我们的发现表明，第599位的突变残基不仅改变了BAY43-9006– BRAF的结合行为，而且对蛋白质的整体动力学行为产生了巨大影响。本文获得的见解可能与设计新的BRAF息息相关抑制剂旨在针对所有BRAF形式获得理想的活性。

更新日期：2018-09-19

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