Decoding the dynamic mechanism of allosteric activation in the cyclin-dependent kinase Cdk2
解读细胞周期蛋白依赖性激酶 Cdk2 变构激活的动态机制
基本信息
- 批准号:10321568
- 负责人:
- 金额:$ 30.8万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAddressAntineoplastic AgentsBindingBiologyCase StudyCell CycleCell Cycle ProgressionCell ProliferationCell physiologyChemicalsClinicClinicalComplexCouplingCrystallizationCyclic AMP-Dependent Protein KinasesCyclin-Dependent KinasesCyclinsDataDevelopmentDiseaseDrug DesignElementsEquilibriumEukaryotic CellFamilyFluorescence Resonance Energy TransferFoundationsG1 PhaseGoalsHumanKineticsLigandsLinkMalignant NeoplasmsMapsMeasuresMediatingMethodsMolecularMolecular ConformationMotionNatureNuclear Magnetic ResonanceOncogenicOpticsPharmaceutical PreparationsPhase TransitionPhosphorylationPhosphotransferasesPopulationPositioning AttributeProcessProtein DynamicsProtein KinaseProteinsRegulationRelaxationResistanceResolutionRoentgen RaysRoleSamplingSignal TransductionSignaling ProteinSpectrum AnalysisStructureTestingTherapeuticWorkcancer therapycell growthcombatconformational conversiondesignexperimental studyinhibitorinsightkinase inhibitormonomernext generationnoveloverexpressionpublic health relevancesmall moleculetargeted treatmenttime usetumorigenesis
项目摘要
Project Abstract
This project reaches towards a new paradigm for how conformational dynamics of protein kinases drive
their catalytic activation, and provides an important case study of how protein dynamics can be commandeered
to artificially control kinase activity with allosteric small molecules.
The protein kinases are a large family of signaling proteins that control cell growth and proliferation in all
eukaryotic cells. Kinases behave like molecular switches, transitioning between catalytically active “on” and
inactive “off” states in a tightly controlled fashion to bring about prescribed changes in cell physiology. This
stringent regulatory control is widely disrupted in cancer, and targeting aberrant kinase activity with small-
molecule drugs is now an important component of many cancer treatments.
Crystal structures have given us static pictures of the on and off states of kinases, but they tell us little
about how the proteins transition between these states, which is an inherently dynamic process. The nature of
these dynamic transitions and how they are perturbed in disease remain largely obscure, a fact that has
impeded our ability to design allosteric therapeutics that switch kinases to the off state by mimicking their
natural control mechanisms. Instead, existing kinase inhibitors work by binding to the highly conserved active
site, a mode of action that makes them poorly selective.
The goal of this project is to use a combination of experimental methods that provide complementary
information about protein dynamics to determine how kinases transition between different conformational
states, and to understand how kinase dynamics can be commandeered by small-molecule drugs to artificially
modulate kinase function. Using nuclear magnetic resonance and optical spectroscopy applied to the cyclin-
dependent kinase Cdk2, a key regulator of cell cycle progression, we aim to reveal 1) the allosteric coupling
mechanism that links cyclin binding to activation of Cdk2, 2) how phosphorylation cooperates with the cyclin
subunit to tune protein dynamics and promote catalytic activity, and 3) how dynamic conformational changes in
Cdk2 control access of small-molecule ligands to allosteric pockets in the kinase. The insights from this work
will fundamentally advance our understanding of allosteric control mechanisms in proteins, and help set the
stage for the design of advanced allosteric therapeutics that effectively harness allostery to modulate kinase
function.
项目摘要
该项目旨在为蛋白激酶的构象动力学如何驱动
它们的催化激活,并提供了一个重要的案例研究如何蛋白质动力学可以征用
用变构小分子人工控制激酶活性。
蛋白激酶是一个大家族的信号蛋白,控制细胞的生长和增殖,在所有
真核细胞激酶的行为就像分子开关,在催化活性的“开”和“关”之间转换。
以严格控制的方式处于非活性的“关闭”状态,从而在细胞生理学中引起规定的变化。这
在癌症中,严格的调节控制被广泛破坏,并且以小的-
分子药物现在是许多癌症治疗的重要组成部分。
晶体结构给了我们激酶的开和关状态的静态图像,但它们告诉我们的很少
关于蛋白质如何在这些状态之间转换,这是一个内在的动态过程。的性质
这些动态转变以及它们在疾病中是如何被扰乱的,在很大程度上仍然是不清楚的,这一事实已经
阻碍了我们设计变构疗法的能力,这种疗法通过模仿激酶的功能,
自然控制机制。相反,现有的激酶抑制剂通过结合高度保守的活性蛋白来起作用。
地点,一种使他们选择性差的行动模式。
这个项目的目标是使用一个实验方法的组合,提供互补的
关于蛋白质动力学的信息,以确定激酶如何在不同构象之间转换
国家,并了解如何激酶动力学可以征用小分子药物,人工
调节激酶功能。利用核磁共振和光谱技术,
依赖性激酶Cdk 2是细胞周期进程的关键调节因子,我们的目的是揭示:1)
2)磷酸化如何与细胞周期蛋白协同作用
亚基来调节蛋白质动力学和促进催化活性,以及3)在蛋白质中如何动态构象变化。
cdk 2控制小分子配体进入激酶的变构口袋。这项工作的启示
将从根本上推进我们对蛋白质变构控制机制的理解,并有助于建立
设计有效利用变构调节激酶的高级变构治疗剂的阶段
功能
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Allostery governs Cdk2 activation and differential recognition of CDK inhibitors.
- DOI:10.1038/s41589-020-00725-y
- 发表时间:2021-04
- 期刊:
- 影响因子:14.8
- 作者:Majumdar A;Burban DJ;Muretta JM;Thompson AR;Engel TA;Rasmussen DM;Subrahmanian MV;Veglia G;Thomas DD;Levinson NM
- 通讯作者:Levinson NM
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Nicholas Mark Levinson的其他文献
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{{ truncateString('Nicholas Mark Levinson', 18)}}的其他基金
Targeting allosteric scaffolding functions of Aurora kinase A in cancer
靶向癌症中极光激酶 A 的变构支架功能
- 批准号:
10373096 - 财政年份:2021
- 资助金额:
$ 30.8万 - 项目类别:
A transformative drug discovery platform for allosteric kinase inhibitors
变构激酶抑制剂的变革性药物发现平台
- 批准号:
10595089 - 财政年份:2021
- 资助金额:
$ 30.8万 - 项目类别:
A transformative drug discovery platform for allosteric kinase inhibitors
变构激酶抑制剂的变革性药物发现平台
- 批准号:
10097782 - 财政年份:2021
- 资助金额:
$ 30.8万 - 项目类别:
Targeting allosteric scaffolding functions of Aurora kinase A in cancer
靶向癌症中极光激酶 A 的变构支架功能
- 批准号:
10210065 - 财政年份:2021
- 资助金额:
$ 30.8万 - 项目类别:
Targeting allosteric scaffolding functions of Aurora kinase A in cancer
靶向癌症中极光激酶 A 的变构支架功能
- 批准号:
10593935 - 财政年份:2021
- 资助金额:
$ 30.8万 - 项目类别:
A transformative drug discovery platform for allosteric kinase inhibitors
变构激酶抑制剂的变革性药物发现平台
- 批准号:
10360449 - 财政年份:2021
- 资助金额:
$ 30.8万 - 项目类别:
Time-resolved FRET-based allostery sensors for any protein kinase drug target
适用于任何蛋白激酶药物靶标的时间分辨 FRET 变构传感器
- 批准号:
9887709 - 财政年份:2020
- 资助金额:
$ 30.8万 - 项目类别:
Time-resolved FRET-based allostery sensors for any protein kinase drug target
适用于任何蛋白激酶药物靶标的时间分辨 FRET 变构传感器
- 批准号:
10348717 - 财政年份:2020
- 资助金额:
$ 30.8万 - 项目类别:
Kinome-Wide Spectroscopic Study of Drug Binding Site Electrostatics
药物结合位点静电的全激酶组光谱研究
- 批准号:
8351780 - 财政年份:2012
- 资助金额:
$ 30.8万 - 项目类别:
Kinome-Wide Spectroscopic Study of Drug Binding Site Electrostatics
药物结合位点静电的全激酶组光谱研究
- 批准号:
8973668 - 财政年份:2012
- 资助金额:
$ 30.8万 - 项目类别:
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