Interaction of substrates and inhibitors with tousled-like kinase 2

底物和抑制剂与蓬乱样激酶 2 的相互作用

基本信息

  • 批准号:
    9813105
  • 负责人:
  • 金额:
    $ 16.75万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-15 至 2020-08-14
  • 项目状态:
    已结题

项目摘要

ABSTRACT Tousled-like kinases (TLKs) are poorly studied nuclear serine-threonine kinases essential to proper cell division and overall viability in animals. Humans have two TLK isozymes, TLK1 and TLK2 (TLK1/2), that are closely related and thought to have redundant roles in genome maintenance. In addition to having key roles in normal cell physiology, dysregulation of TLKs has also been implicated in human disease: TLK2 haploinsufficiency causes a distinct neurodevelopmental disorder, and TLK1/2 upregulation drives cancer cell proliferation. Though TLKs have ascribed roles during DNA synthesis, other critical functions of the kinases in the cell cycle and in responses to DNA damage are poorly understood. A more complete understanding of TLK1/2 function has been hampered by 1) an absence of potent and specific small molecule inhibitors for use as tool compounds to allow temporal control of kinase activity and 2) limited knowledge of direct in vivo substrates of the kinases. The aim of this pilot project is to address these deficiencies through solution of X-ray crystal structures of TLK2-inhibitor and TLK2-substrate complexes, and by identification of new TLK substrates through unbiased screens. Screening a focused kinase inhibitor library, we have identified a set of small molecule TLK2 inhibitors. We will optimize established conditions for growing obtain crystals of TLK2-inhibitor complexes, and solve their high resolution structures. To understand the structural basis for selective substrate targeting, we will map interactions between TLK2 and its best-characterized substrate, ASF1a, and solve structures of TLK2 in complex with synthetic and ASF1a-derivied peptide substrates. We will use a chemical genetic approach to identify new TLK2 substrates. An analog-sensitive TLK2 allele will be used with N6- substituted analogs of ATP--S to thiophosphorylate its direct substrates in intact cell nuclei. Tryptic thiophosphorylated peptides will be isolated by covalent capture and release, and then identified by LC-MS/MS analysis. These studies will set the stage for future studies investigations of the cellular function of newly identified substrates. and provide a basis for structure-guided elaboration of potent and specific inhibitors.
摘要

项目成果

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DAVID A CALDERWOOD其他文献

DAVID A CALDERWOOD的其他文献

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{{ truncateString('DAVID A CALDERWOOD', 18)}}的其他基金

Integrin Trafficking to Focal Adhesions
整合素运输至局部粘连
  • 批准号:
    10557823
  • 财政年份:
    2020
  • 资助金额:
    $ 16.75万
  • 项目类别:
Integrin Trafficking to Focal Adhesions
整合素运输至局部粘连
  • 批准号:
    9973391
  • 财政年份:
    2020
  • 资助金额:
    $ 16.75万
  • 项目类别:
Integrin Trafficking to Focal Adhesions
整合素运输至局部粘连
  • 批准号:
    10330379
  • 财政年份:
    2020
  • 资助金额:
    $ 16.75万
  • 项目类别:
2011 Fibronectin, Integrins and Related Molecules GRC/GRS
2011 纤连蛋白、整合素及相关分子 GRC/GRS
  • 批准号:
    8125512
  • 财政年份:
    2011
  • 资助金额:
    $ 16.75万
  • 项目类别:
Integrin-Filamin Interactions in Migration and Signaling
整合素-细丝蛋白在迁移和信号传导中的相互作用
  • 批准号:
    7931117
  • 财政年份:
    2009
  • 资助金额:
    $ 16.75万
  • 项目类别:
Identification of beta 1 integrin activating proteins
β1 整合素激活蛋白的鉴定
  • 批准号:
    7293763
  • 财政年份:
    2007
  • 资助金额:
    $ 16.75万
  • 项目类别:
Identification of beta 1 integrin activating proteins
β1 整合素激活蛋白的鉴定
  • 批准号:
    7449516
  • 财政年份:
    2007
  • 资助金额:
    $ 16.75万
  • 项目类别:
Integrin-filamin Interactions in Migration and Signaling
整合素-细丝蛋白在迁移和信号转导中的相互作用
  • 批准号:
    6928000
  • 财政年份:
    2003
  • 资助金额:
    $ 16.75万
  • 项目类别:
Filamin interactions in differentiation, invasion and disease
细丝蛋白在分化、侵袭和疾病中的相互作用
  • 批准号:
    8437332
  • 财政年份:
    2003
  • 资助金额:
    $ 16.75万
  • 项目类别:
Integrin-Filamin Interactions in Migration and Signaling
整合素-细丝蛋白在迁移和信号传导中的相互作用
  • 批准号:
    8052740
  • 财政年份:
    2003
  • 资助金额:
    $ 16.75万
  • 项目类别:
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