Molecular Diversity ( IF 3.9 ) Pub Date : 2021-01-03 , DOI: 10.1007/s11030-020-10179-y Shan Du 1 , Xin-Hua Lu 2 , Wei-Ya Li 1 , Li-Peng Li 1 , Yang-Chun Ma 1 , Liang Zhou 1 , Jing-Wei Wu 1 , Ying Ma 1 , Run-Ling Wang 1
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Abstract
The E69K mutation is one of the most frequent protein tyrosine phosphatase-2 (SHP2) mutations in leukemia, and it can cause the increase in the protein activity. Recent studies have shown that the E69K mutation was fairly sensitive to the allosteric inhibitor of SHP2 (SHP099). However, the molecular mechanism of the allosteric drug SHP099 inhibiting SHP2E69K remains unclear. Thus, the molecular dynamic simulations and the post-dynamics analyses (RMSF, PCA, DCCM, RIN and the binding free energies) for SHP2WT, SHP2WT-SHP099, SHP2E69K and SHP2E69K-SHP099 were carried out, respectively. Owing to the strong binding affinity of SHP099 to residues Thr219 and Arg220, the flexibility of linker region (residues Val209-Arg231) was reduced. Moreover, the presence of SHP099 kept the autoinhibition state of the SHP2 protein through enhancing the interactions between the linker region and Q loop in PTP domain, such as Thr219/Val490, Thr219/Asn491, Arg220/Ile488 and Leu254/Asn491. In addition, it was found that the residues (Thr219, Arg220, Leu254 and Asn491) might be the key residues responsible for the conformational changes of protein. Overall, this study may provide an important basis for understanding how the SHP099 effectively inhibited the SHP2E69K activity at the molecular level.
Graphical abstract
中文翻译：
变构药物SHP099抑制SHP2 E69K的动力学机制探究
摘要
E69K突变是白血病中最常见的蛋白酪氨酸磷酸酶2（SHP2）突变之一，可引起蛋白活性增加。最近的研究表明，E69K 突变对 SHP2 变构抑制剂 (SHP099) 相当敏感。然而，变构药物 SHP099 抑制 SHP2 E69K的分子机制仍不清楚。因此，SHP2 WT、SHP2 WT -SHP099、SHP2 E69K和 SHP2 E69K的分子动力学模拟和后动力学分析（RMSF、PCA、DCCM、RIN 和结合自由能）-SHP099 分别进行。由于 SHP099 对残基 Thr219 和 Arg220 的强结合亲和力，接头区域（残基 Val209-Arg231）的灵活性降低。此外，SHP099 的存在通过增强连接区与 PTP 域中 Q 环之间的相互作用，例如 Thr219/Val490、Thr219/Asn491、Arg220/Ile488 和 Leu254/Asn491，保持了 SHP2 蛋白的自抑制状态。此外，还发现残基（Thr219、Arg220、Leu254 和 Asn491）可能是导致蛋白质构象变化的关键残基。总的来说，这项研究可能为理解 SHP099 如何在分子水平上有效抑制 SHP2 E69K活性提供重要基础。
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