Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de la Escuela Superior de Medicina, Instituto Politécnico Nacional, Plan de San Luis Y Díaz Mirón S/N, Col. Casco de Santo Tomas , México City , México.
J Biomol Struct Dyn. 2019 Oct;37(17):4671-4684. doi: 10.1080/07391102.2018.1558112. Epub 2019 Jan 11.
The L858R mutation in EGFR is particularly responsive to small tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. This efficacy decreases due to drug resistance conferred by a second mutation, T790M, which subsequently produces a double mutant, L858R/T790M. Although this resistance was initially attributed to steric blocking by the T790M mutation, experimental studies have demonstrated that differences in the binding affinities of TKIs to T790M and L858R/T790M mutants are more a result of the increased sensitivity of these mutants to ATP than to a decrease in the affinity to TKIs. Regrettably, detailed information at the atomic level on the origins of the increased binding affinity of mutants for ATP is lacking. In this study, we have combined structural data and molecular dynamics simulations with the MMGBSA approach to determine how the L858R, T790M and L858R/T790 mutations impact the binding mechanism of ATP with respect to wild-type EGFR. Structural and energetic analyses provided novel information that helps to explain the increased affinity of ATP to T790M and L858R/T790 mutants with respect to L858R and wild-type systems. In addition, it was observed that dimerization of the wild-type and mutant systems exerts dissimilar effects on the ATP binding affinity characteristic of negative cooperativity. Communicated by Ramaswamy H. Sarma.
EGFR 中的 L858R 突变特别对小的酪氨酸激酶抑制剂（TKI）如吉非替尼和厄洛替尼敏感。这种疗效由于第二个突变 T790M 导致的耐药性而降低，这随后产生了一个双突变体，L858R/T790M。虽然这种耐药性最初归因于 T790M 突变的空间位阻，但实验研究表明，TKI 与 T790M 和 L858R/T790M 突变体的结合亲和力的差异更多地是由于这些突变体对 ATP 的敏感性增加，而不是 TKI 亲和力的降低。遗憾的是，关于突变体对 ATP 结合亲和力增加的原子水平的详细信息尚不清楚。在这项研究中，我们结合结构数据和分子动力学模拟以及 MMGBSA 方法，确定了 L858R、T790M 和 L858R/T790M 突变如何影响野生型 EGFR 中 ATP 的结合机制。结构和能量分析提供了新的信息，有助于解释 T790M 和 L858R/T790 突变体与 L858R 和野生型系统相比对 ATP 的亲和力增加。此外，观察到野生型和突变型系统的二聚化对负协同作用特征的 ATP 结合亲和力产生了不同的影响。由 Ramaswamy H. Sarma 传达。
