Allosteric networks governing regulation and catalysis of Src-family protein tyrosine kinases: Implications for disease-associated kinases
Allosteric networks governing regulation and catalysis of Src-family protein tyrosine kinases: Implications for disease-associated kinases
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DOI：
10.1111/j.1440-1681.2009.05237.x
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发表时间：
2010-01-01
影响因子：
2.9
通讯作者：
Culvenor, Janetta G.
中科院分区：
文献类型：
--
作者：
Cheng, Heung-Chin;Johnson, Timothy M.;Culvenor, Janetta G.
P > 1。src家族蛋白酪氨酸激酶（SFKs）是多结构域致癌蛋白酪氨酸激酶。它们的过度激活有助于癌症的形成和发展。因此，sfk的合成抑制剂正被开发为癌症治疗的治疗药物。了解SFK的调控和催化机制是开发治疗性SFK抑制剂的必要条件。虽然已经确定了sfk的许多上游调节因子和蛋白质底物，但sfk的激活和催化机制尚不完全清楚。特别是，不活跃的sfk在激活过程中如何发生构象转变尚不清楚。在催化过程中控制底物结合和产物释放的机制是另一个需要研究的领域。最近的一些出版物表明，在SFKs的激酶结构域中存在由四个保守的相互作用的疏水残基形成的“疏水脊”。在本综述中，我们讨论了疏水棘残基的组装和拆卸如何控制sfk在激活过程中的构象转变。除了激酶活性的调节外，疏水棘也参与催化作用。最近有人假设，对疏水脊残基的扰动是催化的关键步骤。进一步研究疏水脊柱残基在SFK调控和催化中的作用将有助于开发用于癌症治疗的SFK抑制剂。
P>1. The Src-family protein tyrosine kinases (SFKs) are multidomain oncogenic protein tyrosine kinases. Their overactivation contributes to cancer formation and progression. Thus, synthetic inhibitors of SFKs are being developed as therapeutics for cancer treatment. Understanding the regulatory and catalytic mechanisms of SFKs is necessary for the development of therapeutic SFK inhibitors.2. Although many upstream regulators and protein substrates of SFKs have been identified, both the mechanisms of activation and catalysis of SFKs are not fully understood. In particular, it is still unclear how the inactive SFKs undergo conformational transition during activation. The mechanism governing the binding of substrates and the release of products during catalysis is another area that requires investigation.3. Several recent publications indicate the presence of a 'hydrophobic spine' formed by four conserved interacting hydrophobic residues in the kinase domain of SFKs. In the present review, we discuss how the assembly and disassembly of the hydrophobic spine residues may govern conformational transition of SFKs during activation. In addition to regulation of kinase activity, the hydrophobic spine is implicated to be involved in catalysis. It has been postulated recently that perturbation of the hydrophobic spine residues is a key step in catalysis.4. Further investigations to decipher the roles of the hydrophobic spine residues in regulation and catalysis of SFKs will benefit the development of therapeutic SFK inhibitors for cancer treatment.