Structure and functional mechanisms of molecular chaperones and protein kinases
分子伴侣和蛋白激酶的结构和功能机制
基本信息
- 批准号:9920188
- 负责人:
- 金额:$ 75.38万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-05-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:ActinsAddressAffinityArchitectureBCR/ABL fusion geneBiochemicalBiological ProcessCell AdhesionCellsChimeric ProteinsChronic Myeloid LeukemiaClientComplexDNA DamageDrug resistanceHuman GenomeMediatingMolecular ChaperonesMolecular StructureNMR SpectroscopyPharmaceutical PreparationsPhosphotransferasesProtein DynamicsProtein FamilyProtein KinaseProtein Tyrosine KinaseProteinsProteomeReportingResolutionRoleStructureTherapeutic InterventionWorkbiophysical techniquescell motilityfascinategene productnon-Nativenovelpathogenic bacteriaprotein aggregationresistance mutationresponsetargeted treatment
项目摘要
PROJECT SUMMARY
Our lab works on two main directions: first, the determination of the structural and dynamic basis for
the function and assembly of large protein machineries; and second, the determination of the role of
internal protein dynamics in regulating protein activity and allosteric interactions. We propose to use
NMR spectroscopy, together with other biochemical and biophysical techniques, to determine at the
atomic resolution the mechanisms underpinning the function of two important protein families:
molecular chaperones and protein kinases.
Molecular chaperones are central to maintaining a functional proteome in the cell by rescuing non-
native proteins from aggregation and misfolding and assisting with their folding. Our lab reported the
first ever high resolution structures of molecular chaperones in complex with unfolded proteins. We
will determine the structures of important chaperones such as the Hsp40, Hsp70 and Hsp90 in
complex with client proteins. We wish to address how different chaperones engage non-native
proteins and how distinct chaperone architectures may alter activity.
The Abl kinase holds a prominent place among the over 500 protein kinases encoded by the human
genome. Abl mediates its function by participating in a number of biological processes, including
actin remodeling, cell adhesion and motility, DNA damage response, and bacterial pathogen
response. The Bcr-Abl fusion gene product has constitutive tyrosine kinase activity and causes chronic
myeloid leukemia (CML). We will use NMR to provide fascinating, novel information about the
regulatory and activation mechanisms of this important kinase. We will study how drug-resistance
mutations exert their effect in lowering the drug affinity for Abl.
项目摘要
我们的实验室工作在两个主要方向:第一,确定结构和动态基础,
大型蛋白质机器的功能和组装;第二,
调节蛋白质活性和变构相互作用的内部蛋白质动力学。我们建议使用
NMR光谱法,连同其他生物化学和生物物理技术,以确定在
原子分辨率支持两个重要蛋白质家族功能的机制:
分子伴侣和蛋白激酶。
分子伴侣是维持细胞中功能蛋白质组的核心,
天然蛋白质聚集和错误折叠,并协助其折叠。我们的实验室报告说
第一个高分辨率的分子伴侣结构与未折叠蛋白质的复合物。我们
将确定重要的分子伴侣的结构,如Hsp 40,Hsp 70和Hsp 90,
与客户蛋白质的复合物。我们希望解决不同的伴侣如何参与非本地
蛋白质以及不同的分子伴侣结构如何改变活性。
Abl激酶在由人类基因编码的超过500种蛋白激酶中占有突出的位置。
基因组Abl通过参与许多生物过程来介导其功能,包括
肌动蛋白重塑、细胞粘附和运动、DNA损伤反应和细菌病原体
反应Bcr-Abl融合基因产物具有组成型酪氨酸激酶活性,并引起慢性炎症。
骨髓性白血病(CML)。我们将使用核磁共振提供迷人的,新颖的信息,
这一重要激酶的调节和激活机制。我们将研究抗药性
突变在降低对药物的依赖性方面发挥作用。
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)
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CHARALAMPOS KALODIMOS其他文献
CHARALAMPOS KALODIMOS的其他文献
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{{ truncateString('CHARALAMPOS KALODIMOS', 18)}}的其他基金
Structure and functional mechanisms of molecular chaperones and protein kinases
分子伴侣和蛋白激酶的结构和功能机制
- 批准号:
9515515 - 财政年份:2017
- 资助金额:
$ 75.38万 - 项目类别:
Structure and functional mechanisms of molecular chaperones and protein kinases
分子伴侣和蛋白激酶的结构和功能机制
- 批准号:
10552406 - 财政年份:2017
- 资助金额:
$ 75.38万 - 项目类别:
Allosteric and Transport Mechanisms in TonB-dependent Transporters
TonB 依赖性转运蛋白的变构和转运机制
- 批准号:
9188052 - 财政年份:2015
- 资助金额:
$ 75.38万 - 项目类别:
Allosteric and Transport Mechanisms in TonB-dependent Transporters
TonB 依赖性转运蛋白的变构和转运机制
- 批准号:
9019305 - 财政年份:2015
- 资助金额:
$ 75.38万 - 项目类别:
Structural insight into novel mechanisms of type III secretion
III 型分泌新机制的结构洞察
- 批准号:
8580192 - 财政年份:2011
- 资助金额:
$ 75.38万 - 项目类别:
Structural insight into novel mechanisms of type III secretion
III 型分泌新机制的结构洞察
- 批准号:
8775192 - 财政年份:2011
- 资助金额:
$ 75.38万 - 项目类别:
Structural insight into novel mechanisms of type III secretion
III 型分泌新机制的结构洞察
- 批准号:
10396532 - 财政年份:2011
- 资助金额:
$ 75.38万 - 项目类别:
Structural insight into novel mechanisms of type III secretion
III 型分泌新机制的结构洞察
- 批准号:
8298308 - 财政年份:2011
- 资助金额:
$ 75.38万 - 项目类别:
Structural insight into novel mechanisms of type III secretion
III 型分泌新机制的结构洞察
- 批准号:
8390463 - 财政年份:2011
- 资助金额:
$ 75.38万 - 项目类别:
Structural insight into novel mechanisms of type III secretion
III 型分泌新机制的结构洞察
- 批准号:
8253171 - 财政年份:2011
- 资助金额:
$ 75.38万 - 项目类别:
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