Structural basis for differential regulation and selective inhibition of human CTP synthase 1

人CTP合酶1差异调节和选择性抑制的结构基础

基本信息

  • 批准号:
    10393643
  • 负责人:
  • 金额:
    $ 48.94万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-04-16 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Cellular proliferation increases demand for ribonucleotide pools to provide precursors for increased RNA, DNA, and membrane synthesis. This demand exceeds the capacity of uptake and salvage pathways, and must be met by increased de novo biosynthesis. In particular, lymphocyte proliferation is dependent on increased nucleotide levels, and targeting nucleotide biosynthesis pathways is the basis for a number of highly successful immunosuppressive treatments. CTP Synthase (CTPS) is the key regulatory enzyme in pyrimidine nucleotide biosynthesis. Humans have two CTPS isoforms encoded on separate genes, CTPS1 and CTPS2. While CTPS1 expression is generally increased in proliferative tissues, little else is known about differential roles of the two isoforms or how they are regulated. CTPS1 plays a critical role in the immune response, and loss of function mutations in humans cause severe immunodeficiency. Loss of CTPS1 results in impaired T and B-cell proliferation, but does not have deleterious effects in other human tissues, indicating unique dependence of the immune response on CTPS1 function. Selective inhibition of CTPS1, therefore, is considered a potentially powerful approach to immunosuppressive therapies with limited off-target effects. A number of inhibitors that specifically target CTPS1 have recently been reported, but the mechanisms of inhibition remain unclear. Here, we focus on the structural and functional characterization of CTPS1 and CTPS2 regulation by native allosteric regulators and by selective small molecule inhibitors. This work will provide insight into the control of nucleotide biosynthesis during cellular proliferation, and serve as the basis for design and targeted discovery of novel compounds with potential for immunosuppressive therapies.
项目总结

项目成果

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Justin M Kollman其他文献

Justin M Kollman的其他文献

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{{ truncateString('Justin M Kollman', 18)}}的其他基金

Structure and function of metabolic enzyme assemblies
代谢酶组装体的结构和功能
  • 批准号:
    10621612
  • 财政年份:
    2023
  • 资助金额:
    $ 48.94万
  • 项目类别:
Administrative Supplement
行政补充
  • 批准号:
    10506086
  • 财政年份:
    2021
  • 资助金额:
    $ 48.94万
  • 项目类别:
Structural basis for differential regulation and selective inhibition of human CTP synthase 1
人CTP合酶1差异调节和选择性抑制的结构基础
  • 批准号:
    10598529
  • 财政年份:
    2021
  • 资助金额:
    $ 48.94万
  • 项目类别:
Structural basis for differential regulation and selective inhibition of human CTP synthase 1
人CTP合酶1差异调节和选择性抑制的结构基础
  • 批准号:
    10207218
  • 财政年份:
    2021
  • 资助金额:
    $ 48.94万
  • 项目类别:
'Structure and function of the R-body, a piston-like nanomachine
“活塞式纳米机器 R 体的结构和功能
  • 批准号:
    10166870
  • 财政年份:
    2018
  • 资助金额:
    $ 48.94万
  • 项目类别:
Acquisition of a high resolution, high throughput cryo-electron microscope
购置高分辨率、高通量冷冻电子显微镜
  • 批准号:
    9273775
  • 财政年份:
    2017
  • 资助金额:
    $ 48.94万
  • 项目类别:
Structure and Function of Metabolic Filaments
代谢丝的结构和功能
  • 批准号:
    10370322
  • 财政年份:
    2016
  • 资助金额:
    $ 48.94万
  • 项目类别:
Structure and Function of Metabolic Filaments
代谢丝的结构和功能
  • 批准号:
    10562658
  • 财政年份:
    2016
  • 资助金额:
    $ 48.94万
  • 项目类别:
Structure and Function of Metabolic Filaments
代谢丝的结构和功能
  • 批准号:
    10725069
  • 财政年份:
    2016
  • 资助金额:
    $ 48.94万
  • 项目类别:
Structure and Function of Metabolic Filaments
代谢丝的结构和功能
  • 批准号:
    10576292
  • 财政年份:
    2016
  • 资助金额:
    $ 48.94万
  • 项目类别:

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