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Tyrosine Kinase Activation and Conformational Flexibility: Lessons from Src-Family Tyrosine Kinases
Accounts of Chemical Research ( IF 18.3 ) Pub Date : 2017-04-20 00:00:00 , DOI: 10.1021/acs.accounts.7b00012 Yilin Meng 1 , Matthew P. Pond 1 , Benoît Roux 1
Accounts of Chemical Research ( IF 18.3 ) Pub Date : 2017-04-20 00:00:00 , DOI: 10.1021/acs.accounts.7b00012 Yilin Meng 1 , Matthew P. Pond 1 , Benoît Roux 1
Affiliation
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets. A prototypical system of central interest to understand the regulation of kinase activity is provided by tyrosine kinase c-Src, which belongs to the family of Src-related non-receptor tyrosine kinases (SFKs). Although the broad picture of autoinhibition via the regulatory domains and via the phosphorylation of the C-terminal tail is well characterized from a structural point of view, a detailed mechanistic understanding at the atomic-level is lacking. Advanced computational methods based on all-atom molecular dynamics (MD) simulations are employed to advance our understanding of tyrosine kinase activation.
中文翻译:
酪氨酸激酶激活和构象灵活性:Src系列酪氨酸激酶的经验教训
蛋白质激酶是催化三磷酸腺苷(ATP)分子的γ-磷酸共价转移到底物上的酪氨酸,丝氨酸,苏氨酸或组氨酸残基上的酶,因此可向下游蛋白质网络发送化学信号。它们是调节细胞生长,增殖,代谢,分化和迁移的重要细胞信号转导酶。失调的蛋白激酶活性通常与多种疾病有关,因此使蛋白激酶成为主要的治疗靶标。酪氨酸激酶c-Src提供了一个重要的原型系统,可以了解激酶活性的调节,该系统属于Src相关的非受体酪氨酸激酶(SFK)家族。尽管从结构的角度已经很好地表征了通过调节域和通过C末端尾部的磷酸化进行自抑制的总体情况,但仍缺乏在原子水平上的详细机理理解。基于全原子分子动力学(MD)模拟的高级计算方法被用来增进我们对酪氨酸激酶激活的理解。
更新日期:2017-04-20
中文翻译:
酪氨酸激酶激活和构象灵活性:Src系列酪氨酸激酶的经验教训
蛋白质激酶是催化三磷酸腺苷(ATP)分子的γ-磷酸共价转移到底物上的酪氨酸,丝氨酸,苏氨酸或组氨酸残基上的酶,因此可向下游蛋白质网络发送化学信号。它们是调节细胞生长,增殖,代谢,分化和迁移的重要细胞信号转导酶。失调的蛋白激酶活性通常与多种疾病有关,因此使蛋白激酶成为主要的治疗靶标。酪氨酸激酶c-Src提供了一个重要的原型系统,可以了解激酶活性的调节,该系统属于Src相关的非受体酪氨酸激酶(SFK)家族。尽管从结构的角度已经很好地表征了通过调节域和通过C末端尾部的磷酸化进行自抑制的总体情况,但仍缺乏在原子水平上的详细机理理解。基于全原子分子动力学(MD)模拟的高级计算方法被用来增进我们对酪氨酸激酶激活的理解。