Department of Biochemistry, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5C1, Canada.
Department of Applied Mathematics, The University of Western Ontario, 1151 Richmond Street, London, ON N6A 5B7, Canada.
Int J Mol Sci. 2021 May 20;22(10):5408. doi: 10.3390/ijms22105408.
We have performed 280 μs of unbiased molecular dynamics (MD) simulations to investigate the effects of 12 different cancer mutations on Kelch-like ECH-associated protein 1 (KEAP1) (G333C, G350S, G364C, G379D, R413L, R415G, A427V, G430C, R470C, R470H, R470S and G476R), one of the frequently mutated proteins in lung cancer. The aim was to provide structural insight into the effects of these mutants, including a new class of ANCHOR (additionally NRF2-complexed hypomorph) mutant variants. Our work provides additional insight into the structural dynamics of mutants that could not be analyzed experimentally, painting a more complete picture of their mutagenic effects. Notably, blade-wise analysis of the Kelch domain points to stability as a possible target of cancer in KEAP1. Interestingly, structural analysis of the R470C ANCHOR mutant, the most prevalent missense mutation in KEAP1, revealed no significant change in structural stability or NRF2 binding site dynamics, possibly indicating an covalent modification as this mutant's mode of action.
我们进行了 280 微秒的无偏分子动力学（MD）模拟，以研究 12 种不同癌症突变对 Kelch 样 ECH 相关蛋白 1（KEAP1）（G333C、G350S、G364C、G379D、R413L、R415G、A427V、G430C、R470C、R470H、R470S 和 G476R）的影响，KEAP1 是肺癌中经常发生突变的蛋白质之一。目的是提供对这些突变体影响的结构见解，包括一类新的 ANCHOR（另外与 NRF2 结合的低效能突变体）突变体变体。我们的工作为无法通过实验分析的突变体的结构动力学提供了额外的见解，更全面地描绘了它们的诱变效应。值得注意的是，Kelch 结构域的叶片分析指出稳定性可能是 KEAP1 中癌症的一个潜在靶点。有趣的是，对 R470C ANCHOR 突变体（KEAP1 中最常见的错义突变）的结构分析显示，其结构稳定性或 NRF2 结合位点动力学没有明显变化，这可能表明该突变体的作用模式是共价修饰。
