FGF Receptor Structure, Dynamics and Function
FGF 受体结构、动力学和功能
基本信息
- 批准号:9239910
- 负责人:
- 金额:$ 27.11万
- 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:2017-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 3-KinaseAdultApoptosisBackBindingBiologicalBiological AssayBiological ModelsBiological ProcessBiologyBypassC-terminalCell ProliferationCell Surface ProteinsCellsCellular biologyChemotaxisClinicComprehensionConflict (Psychology)CrystallizationDataDatabasesDepositionDiseaseDrug resistanceEmbryonic DevelopmentEnzymesEquilibriumEventEvolutionExtracellular SpaceFGFR2 geneFGFR4 geneFibroblast Growth Factor ReceptorsFibroblastsGatekeepingGenerationsGlutamic AcidGoalsGrowth DisordersHumanHuman BiologyHybridsHydrogen BondingHydrophobicityIn VitroKnowledgeLeadLigandsLinkLobeMalignant Childhood NeoplasmMalignant NeoplasmsMeasurableMediatingMetabolismMitogen-Activated Protein Kinase KinasesModelingMolecularMolecular ConformationMutationN-terminalNGFR geneNMR SpectroscopyOutputPTB DomainPathogenicityPathway interactionsPharmaceutical PreparationsPhenylalaninePhosphorylationPhosphotransferasesPhysiologicalPopulationProtein DynamicsProtein IsoformsProtein Tyrosine KinaseProteinsReceptor ActivationReceptor Protein-Tyrosine KinasesRecruitment ActivityRegulationReportingResearchResearch Project GrantsResolutionRhabdomyosarcomaRoentgen RaysScaffolding ProteinSignal PathwaySignal TransductionSolidStretchingStructureTailTestingTimeTyrosineValineVertebral columnX-Ray Crystallographyacquired drug resistancebasecell behaviorcell growthequilibrium modelexperimental studyfascinateflexibilitygain of functiongain of function mutationinfancyinsightmutantnovelreceptorresponsesenescencesrc-Family Kinasessuccess
项目摘要
Project Summary
The abundance of crystal structures determined for kinase domains of human receptor tyrosine kinases
(RTKs) deposited in the protein data bank have provided snapshots of these enzymes in both inactive and
active states. However, our knowledge of dynamics of this highly allosteric class of enzymes is still in its
infancy. The overall goal of this proposal is to elucidate the intrinsic and extrinsic allosteric control mechanisms
that underlie tyrosine kinase regulation by using the fibroblast growth factor receptor (FGFR) kinase subfamily
as the model system. FGF signaling fulfills a multitude of diverse biological functions throughout embryonic
development and adulthood by controlling cellular proliferation, differentiation, chemotaxis, apoptosis, and
senescence. Through concerted crystallographic and NMR solution studies of a large set of gain-of-function
mutations, we have recently elucidated a dynamic two-state model for FGFR kinase regulation whereby the
enzyme toggles between an inhibited, conformationally rigid state and a more flexible active state (Molecular
Cell, 2007; Cell Reports, 2013). More recently we have refined this model to show that the concerted action of
four molecular switches forming a long-range allosteric connectivity stretching from the kinase hinge located at
the back of the kinase all the way to the A-loop and catalytic pocket at the front of the kinase regulate the
dynamics and thus the active-inactive equilibrium. These data have provided a solid basis for tackling imminent
problems in our comprehension of RTK signaling that are carefully formulated in each of three aims of this
proposal. In Aim I, we will demonstrate for the first time how differences in intrinsic dynamics of four human
FGFR isoforms account for their distinct signaling potentials, thereby providing a molecular rationale for the
evolution of multimember RTK subfamilies. In Aim II, we will determine how frequently occurring mutations at
the gate-keeper residue, a major hurdle in the clinic for drug-resistance, corrupts the autoinhibitory interactions
and leads to gain-of-function. In Aim III, we will establish the structural and dynamic basis by which FGFR
recruits and phosphorylates its major intracellular substrate, FRS2α and demonstrate for the first time how
intracellular substrate binding can act as an extrinsic factor to regulate intrinsic kinase activity. By using a
hybrid of structural experiments (X-ray crystallography and NMR spectroscopy) and biological assays (in vitro
and in cells), we will accomplish each of the aims described that represent major milestones in the RTK field.
This research will fill several knowledge gaps in our understanding of RTK signaling and hence will have a
powerful and sustained influence in the cellular signaling field.
项目摘要
人受体酪氨酸激酶激动域晶体结构的丰度测定
保存在蛋白质数据库中的(RTK)提供了这些酶在非活性和
活动状态。然而,我们对这种高度变构的酶的动力学的了解仍然在它的
婴儿期。这项建议的总体目标是阐明内在和外在的变构控制机制。
通过使用成纤维细胞生长因子受体(FGFR)激酶亚家族调节酪氨酸激酶
作为模型系统。成纤维细胞生长因子信号在整个胚胎过程中发挥多种不同的生物学功能
通过控制细胞的增殖、分化、趋化、凋亡和
衰老。通过协同结晶学和核磁共振溶液研究了一大套功能增益
突变,我们最近阐明了FGFR激酶调节的动态两态模型,通过该模型,
酶在受抑制的构象刚性状态和更灵活的活性状态之间切换(分子
Cell,2007;Cell Reports,2013)。最近,我们改进了这个模型,以表明
四个分子开关形成了从位于
该酶的后面一直到A环和位于该酶前面的催化口袋调节
动力学,从而实现主动-非主动的平衡。这些数据为解决迫在眉睫的问题提供了坚实的基础
我们对RTK信号的理解中的问题,在这三个目标中的每一个中都有仔细的表述
求婚。在目标I中,我们将首次展示四个人的内在动力学的差异
FGFR亚型解释了它们不同的信号潜力,从而为
多成员RTK亚家族的进化。在AIM II中,我们将确定发生突变的频率
门卫残留物是临床耐药的主要障碍,破坏了自身抑制相互作用。
并导致功能增益。在目标三中,我们将建立FGFR的结构和动态基础
招募并磷酸化其主要细胞内底物FRS2α,并首次展示如何
细胞内底物结合可以作为一种外在因素来调节内在的激酶活性。通过使用
结构实验(X射线结晶学和核磁共振光谱学)和生物分析(体外)相结合
在单元中),我们将实现所描述的代表RTK领域主要里程碑的每个目标。
这项研究将填补我们对RTK信令理解中的几个知识空白,因此将有
在细胞信号领域具有强大而持久的影响力。
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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MOOSA MOHAMMADI其他文献
MOOSA MOHAMMADI的其他文献
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{{ truncateString('MOOSA MOHAMMADI', 18)}}的其他基金
FGF Receptor Structure, Dynamics and Function
FGF 受体结构、动力学和功能
- 批准号:
9985425 - 财政年份:2017
- 资助金额:
$ 27.11万 - 项目类别:
Mechanisms of FGF Receptor Regulation and Signaling
FGF 受体调节和信号转导机制
- 批准号:
8727233 - 财政年份:2013
- 资助金额:
$ 27.11万 - 项目类别:
2010 Fibroblast Growth Factors in Development and Diseases Gordon Research Confer
2010 发育和疾病中的成纤维细胞生长因子戈登研究大会
- 批准号:
7915058 - 财政年份:2010
- 资助金额:
$ 27.11万 - 项目类别:
Mechanisms of FGF Receptor Regulation and Signaling
FGF 受体调节和信号转导机制
- 批准号:
6920382 - 财政年份:2000
- 资助金额:
$ 27.11万 - 项目类别:
Mechanisms of FGF Receptor Regulation and Signaling
FGF 受体调节和信号转导机制
- 批准号:
8487214 - 财政年份:2000
- 资助金额:
$ 27.11万 - 项目类别:
Mechanisms of FGF Receptor Regulation and Signaling
FGF 受体调节和信号转导机制
- 批准号:
7066045 - 财政年份:2000
- 资助金额:
$ 27.11万 - 项目类别:
Mechanisms of FGF Receptor Regulation and Signaling
FGF 受体调节和信号转导机制
- 批准号:
8092615 - 财政年份:2000
- 资助金额:
$ 27.11万 - 项目类别:
MECHANISMS OF FGF RECEPTOR REGULATION AND SIGNALING
FGF 受体调节和信号转导机制
- 批准号:
6634685 - 财政年份:2000
- 资助金额:
$ 27.11万 - 项目类别:
MECHANISMS OF FGF RECEPTOR REGULATION AND SIGNALING
FGF 受体调节和信号转导机制
- 批准号:
6516608 - 财政年份:2000
- 资助金额:
$ 27.11万 - 项目类别:
Mechanisms of FGF Receptor Regulation and Signaling
FGF 受体调节和信号转导机制
- 批准号:
7456452 - 财政年份:2000
- 资助金额:
$ 27.11万 - 项目类别:
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