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Nuclear magnetic resonance analysis of the conformational state of cancer mutant of fibroblast growth factor receptor 1 tyrosine kinase domain

机译:成纤维细胞生长因子受体1酪氨酸激酶结构域癌症突变体构象状态的核磁共振分析

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摘要

Tyrosine kinases are key enzymes that play critical roles in growth signaling, the abnormal activation of which is associated with various human cancers. Activation of tyrosine kinases is mediated by tyrosine phosphorylation in the activation-loop, which transforms the catalytic domain to the active state conformation. Cancer mutations are supposed to transform the conformation of the catalytic domain into the active-form independent of the phosphorylation state of the activation-loop. Here, we report structural and biophysical analyses of cancer mutations of the tyrosine kinase domain of fibroblast growth factor receptor 1 (FGFR1). Based on the nuclear magnetic resonance analyses, phosphorylation of the activation-loop exhibited cooperative structural transition in the activation-loop, C-helix and P-loop regions, whereas cancer mutations induced structural transformation at either one or two of these regions.
机译:酪氨酸激酶是在生长信号中起关键作用的关键酶,其异常激活与各种人类癌症有关。酪氨酸激酶的激活是由激活环中的酪氨酸磷酸化介导的,该环将催化结构域转化为活性状态构象。据推测,癌症突变可将催化结构域的构象转化为活性形式,而与激活环的磷酸化状态无关。在这里,我们报告成纤维细胞生长因子受体1(FGFR1)酪氨酸激酶域的癌症突变的结构和生物物理分析。根据核磁共振分析,激活环的磷酸化在激活环,C螺旋和P环区域表现出协同的结构转变,而癌症突变诱导了这些区域之一或两个的结构转变。

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