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首页> 美国卫生研究院文献>ACS Omega >Three Novel Mutations I65S R66S and G86R DivulgeSignificant Conformational Variations in the PTB Domain of the IRS1Gene
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Three Novel Mutations I65S R66S and G86R DivulgeSignificant Conformational Variations in the PTB Domain of the IRS1Gene

机译：三种新颖的突变I65SR66S和G86R泄漏IRS1的PTB域中的显着构象变化基因

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Insulin receptor substrate 1 (IRS1) is one of the major substrates for the IR, and their interaction mediates several downstream insulin signaling pathways. In this study, we have identified three novel mutations in the IRS1 gene of type 2 diabetic (T2D) patients, which reflected in the amino acid changes as I65S, R66S, and G86R in the phosphotyrosine binding domain of the IRS1 protein. The impact of these mutations on the structure and function of the IRS1 protein was evaluated through molecular modeling studies, and distinct conformational fluctuations were recorded. The variable binding affinities and positional displacement of these mutant models were observed in the ligand-binding cleft of IR. The mutant IRS1 models triggered conformational changes in the L1 domain of IR upon their binding. Such structural variations in IRS1 and IR structures due to mutations resulted in variable molecular interactions that could lead to altered insulin transduction, followed by insulin resistance and T2D.
机译：胰岛素受体底物1（IRS1）是IR的主要底物之一，它们的相互作用介导了多个下游胰岛素信号通路。在这项研究中，我们确定了2型糖尿病（T2D）患者的IRS1基因中的三个新突变，这反映在IRS1蛋白的磷酸酪氨酸结合域中的氨基酸变化为I65S，R66S和G86R。通过分子建模研究评估了这些突变对IRS1蛋白结构和功能的影响，并记录了明显的构象波动。在IR的配体结合裂隙中观察到这些突变体模型的可变结合亲和力和位置位移。突变的IRS1模型在结合后触发IR L1结构域的构象变化。由于突变，IRS1和IR结构中的这种结构变化导致可变的分子相互作用，这可能导致胰岛素转导发生变化，进而导致胰岛素抵抗和T2D。

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