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
- 来源:
- 关键词:Active SitesAdoptedAffinityAnabolismAutoimmune DiseasesB Cell ProliferationBindingBinding SitesBiochemicalBiological AssayBiophysicsBypassC-terminalCell ProliferationCellsCellular AssayChemicalsComplexCryoelectron MicroscopyDNA biosynthesisDefectDependenceDevelopmentDiseaseDissectionDrug TargetingEnzyme Inhibitor DrugsEnzymesFailureFeedbackGenesGrowthHumanHyperactivityImmune responseImmune systemImmunologic Deficiency SyndromesImmunosuppressionImmunosuppressive AgentsImpairmentInheritedLearningLeukocytesLymphocyte CountMetabolismMolecularMolecular ConformationMutagenesisNucleotide BiosynthesisNucleotidesPathway interactionsPeptidesPharmaceutical PreparationsPhosphorylationPhysiologicalPlayProductionProtein IsoformsPyrimidine NucleotidesRNA chemical synthesisRegulationReportingResolutionRibonucleotidesRoleSolidSpecificityStructureT-LymphocyteTailTestingTherapeutic immunosuppressionTissuesWorkbasebiophysical propertiesdesigndrug developmentflexibilityhuman tissueimprovedin vitro activityinhibitorinsightloss of function mutationlymphocyte proliferationmembrane synthesisnovelnovel therapeuticsorgan transplant rejectionpathogenpreventscaffoldside effectsmall molecule inhibitorsuccesstherapeutic developmenttooluptake
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
细胞增殖增加了对核糖核酸库的需求,以提供增加的RNA,DNA,
和膜合成。这一需求超出了吸收和打捞途径的能力,必须
伴随着新生物合成的增加。特别是,淋巴细胞的增殖依赖于
核苷酸水平,并靶向核苷酸生物合成途径是许多非常成功的基础
免疫抑制治疗。CTP合成酶(CTPS)是嘧啶核苷酸的关键调节酶
生物合成。人类有两种CTPS亚型,分别编码在不同的基因上,CTPS1和CTPS2。而当
CTPS1在增生性组织中的表达普遍增加,其他方面对CTPS1的不同作用知之甚少
两种异构体或它们是如何被调控的。CTPS1在免疫应答中起着关键作用,而
人类的功能突变会导致严重的免疫缺陷。CTPS1缺失导致T和B细胞受损
增殖,但对其他人体组织没有有害影响,表明对
CTPS1功能的免疫应答。因此,选择性抑制CTPS1被认为是一种潜在的
有效的免疫抑制治疗方法,具有有限的非靶向效应。一系列的抑制剂
最近报道了特异性靶向CTPS1的研究,但其抑制机制尚不清楚。这里,
我们主要研究天然变构对CTPS1和CTPS2调控的结构和功能特征
调节剂和选择性小分子抑制剂。这项工作将为核苷酸的控制提供洞察力
在细胞增殖过程中的生物合成,并作为设计和有针对性地发现新的
具有免疫抑制治疗潜力的化合物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Justin M Kollman其他文献
Justin M Kollman的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
相似海外基金
How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
- 批准号:
2315783 - 财政年份:2023
- 资助金额:
$ 48.94万 - 项目类别:
Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
- 批准号:
2719534 - 财政年份:2022
- 资助金额:
$ 48.94万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633211 - 财政年份:2020
- 资助金额:
$ 48.94万 - 项目类别:
Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
- 批准号:
20K01113 - 财政年份:2020
- 资助金额:
$ 48.94万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2436895 - 财政年份:2020
- 资助金额:
$ 48.94万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633207 - 财政年份:2020
- 资助金额:
$ 48.94万 - 项目类别:
Studentship
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
- 批准号:
426559561 - 财政年份:2019
- 资助金额:
$ 48.94万 - 项目类别:
Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
- 批准号:
2236701 - 财政年份:2019
- 资助金额:
$ 48.94万 - 项目类别:
Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
- 批准号:
19K01745 - 财政年份:2019
- 资助金额:
$ 48.94万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
- 批准号:
415543446 - 财政年份:2019
- 资助金额:
$ 48.94万 - 项目类别:
Research Fellowships














{{item.name}}会员




