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首页> 外文期刊>RSC Advances >Computational analysis revealing that K634 and T681 mutations modulate the 3D-structure of PDGFR-β and lead to sunitinib resistance
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Computational analysis revealing that K634 and T681 mutations modulate the 3D-structure of PDGFR-β and lead to sunitinib resistance

机译：计算分析表明，K634和T681突变可调节PDGFR-β的3D结构并导致舒尼替尼耐药

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Platelet-derived growth factor receptor-beta (PDGFR-β) is expressed by endothelial cells (ECs) of tumor-associated blood vessels and regulates primarily early hematopoiesis. Human PDGFR-β is a novel therapeutic target for the treatment of glioblastoma. However, a major challenge of glioblastoma therapy is to overcome drug resistance, mostly initiated by missense mutations in the protein kinase catalytic domain. The present work aimed to carry out in silico structural studies on wild-type (WT) and some major mutant-type (MT) PDGFR-β complexes to elucidate the probable mechanism of its resistance related to the anti-angiogenic and anticancer drug sunitinib. In the absence of a crystal structure, the 3D structures of WT and MT PDGFR-β kinase were predicted using homology modeling followed by docking analysis with sunitinib. Molecular dynamics simulations of WT and MT PDGFR-β complexes with sunitinib were performed to understand the differential structural alterations in the PDGFR-β kinase structure, as well as its stability. Our results showed that the overall effect of mutations in the residues K634A, T681M, T681F, T681I, and T681A led to the destabilized 3D structures of PDGFR-β and altered their binding affinities with sunitinib. In particular, the mutation at the gatekeeper residue threonine 681 (T681M), present in the ATP binding pocket, majorly affected the protein stability, thus conferring resistance to the drug sunitinib. Our present findings utilizing in silico approaches show that the differential binding of sunitinib with WT and MT proteins leads to resistance being developed in sunitinib chemotherapy.
机译：血小板衍生的生长因子受体-β（PDGFR-β）由肿瘤相关血管的内皮细胞（EC）表达，并主要调节早期造血功能。人PDGFR-β是治疗胶质母细胞瘤的新型治疗靶标。然而，胶质母细胞瘤治疗的主要挑战是克服耐药性，这主要是由蛋白激酶催化域的错义突变引起的。目前的工作旨在对野生型（WT）和一些主要的突变型（MT）PDGFR-β复合物进行计算机结构研究，以阐明其抗药性的可能机制。 -血管生成和抗癌药物舒尼替尼。在没有晶体结构的情况下，WT和MTPDGFR-β激酶的3D结构可通过同源性建模预测，然后与舒尼替尼进行对接分析。进行了舒尼替尼与WT和MTPDGFR-β复合物的分子动力学模拟，以了解PDGFR-β激酶结构的差异性结构变化及其稳定性。我们的结果表明，残基K634A，T681M，T681F，T681I和T681A突变的整体效果导致PDGFR-β的3D结构不稳定，并改变了它们与舒尼替尼的结合亲和力。特别是，存在于ATP结合袋中的关守残基苏氨酸681（T681M）处的突变主要影响蛋白质的稳定性，因此赋予了对舒尼替尼药物的耐药性。我们目前使用计算机方法的发现表明，舒尼替尼与WT和MT蛋白的差异结合导致舒尼替尼化疗中产生了耐药性。

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