Abstract

Interferon regulatory factor 1 (IRF-1) plays a vital role in cell proliferation and cell differentiation by acting as a tumor suppressor gene and its role is linked to various types of cancers, including leukemia and pre-leukemia myelodysplasia. Mutations in the coding region of the IRF-1 are likely to influence the IRF-1 and its DNA binding affinity. The molecular mechanism of the DNA recognition with the IRF-1 protein upon mutations is still unknown. In this study, we have elucidated the structural and functional behavior of the wild-type and mutant (K75E and E222K) IRF-1 proteins and their corresponding molecular mechanisms with DNA recognition at the molecular level, using molecular dynamics simulations. Furthermore, we also applied the docking approach to examine the binding between the IRF-1 protein and DNA upon mutations. This study evidently explains that, due to mutations, the IRF-1 structure loses its stability and becomes more flexible than the wild-type protein. This structural loss might affect IRF-1-DNA interaction and lead to the inhibition of cancer suppression. Identifying the effects of IRF-1 at the molecular level will be beneficial for designing drugs for IRF-1 associated cancers. These drugs should be designed so that they can help reactivate the IRF-1 function, by increasing the transcriptional activity, to treat leukemia.

摘要

干扰素调节因子 1 (IRF-1) 通过作为肿瘤抑制基因在细胞增殖和细胞分化中发挥重要作用，其作用与各种类型的癌症有关，包括白血病和白血病前期骨髓增生异常。IRF-1 编码区的突变可能会影响 IRF-1 及其 DNA 结合亲和力。突变后 IRF-1 蛋白识别 DNA 的分子机制仍然未知。在这项研究中，我们使用分子动力学模拟阐明了野生型和突变型（K75E 和 E222K）IRF-1 蛋白的结构和功能行为及其在分子水平上与 DNA 识别的相应分子机制。此外，我们还应用对接方法来检查 IRF-1 蛋白和 DNA 在突变时的结合。这项研究清楚地解释了，由于突变，IRF-1结构失去了稳定性，变得比野生型蛋白质更灵活。这种结构损失可能会影响 IRF-1-DNA 相互作用并导致抑制癌症抑制。在分子水平上确定 IRF-1 的作用将有利于设计用于 IRF-1 相关癌症的药物。应该设计这些药物，以便它们可以通过增加转录活性来帮助重新激活 IRF-1 功能，以治疗白血病。在分子水平上确定 IRF-1 的作用将有利于设计用于 IRF-1 相关癌症的药物。应该设计这些药物，以便它们可以通过增加转录活性来帮助重新激活 IRF-1 功能，以治疗白血病。在分子水平上确定 IRF-1 的作用将有利于设计用于 IRF-1 相关癌症的药物。应该设计这些药物，以便它们可以通过增加转录活性来帮助重新激活 IRF-1 功能，以治疗白血病。