Dynamics & energetics of p38a kinase regulation by ligands
动力学
基本信息
- 批准号:8436569
- 负责人:
- 金额:$ 33.53万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-01 至 2017-01-31
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAffinityAlzheimer&aposs DiseaseAmino Acid SequenceAmino AcidsArchitectureBindingBinding SitesC-terminalCalorimetryComplexCoupledCrystallographyDataDevelopmentDiseaseDockingDrug DesignDrug InteractionsEntropyFamilyFoundationsGoalsGrowth FactorHeartHuman BiologyHydrogenKnowledgeLaboratoriesLibrariesLigandsLightLobeMAP Kinase GeneMAP2K6 geneMAPK Signaling Pathway PathwayMAPK14 geneMAPK8 geneMalignant NeoplasmsMeasuresMediatingMethodsMitogen-Activated Protein KinasesModelingMolecular ConformationMolecular StructureMotionNMR SpectroscopyNuclear Magnetic ResonancePathway interactionsPharmaceutical PreparationsPharmacologic SubstancePhosphoric Monoester HydrolasesPhosphotransferasesPositioning AttributeProcessProtein Tyrosine PhosphataseProteinsProxyRadialRegulationRelaxationRenaissanceReportingResolutionRestRheumatoid ArthritisRoleSamplingSideSignal TransductionSiteSpecificityStimulusStructureTechniquesTertiary Protein StructureTestingThermodynamicsTimeTitrationsVertebral columnbasecell typecost effectivecytokinedesignextracellulargenetic regulatory proteinhuman diseaseimprovedinformation gatheringinhibitor/antagonistinsightmannervous system disordernovelpressureprotein complexprotein structurepublic health relevanceresearch studyresponsesmall molecule
项目摘要
DESCRIPTION (provided by applicant): High-affinity protein complexes are critical to a large number of intricate regulatory processes. Their formation involves a complicated manifold of interactions that are diverse and complex. This complexity is reflected in the difficulty of computing the energetics of interactions between proteins using molecular structure alone. Indeed, the structure-based design of pharmaceuticals has been significantly impeded by this barrier. Understanding the fundamental origins of the energetics and dynamics of the interactions of proteins with both natural and pharmacological ligands is clearly critical to the optimization of "rational" drug design. Recent advances in nuclear magnetic resonance (NMR) relaxation methods have enabled the use of measures-of-motion between conformational states of a protein as a proxy for conformational entropy. There is now a strong indication from recent studies utilizing this approach that changes in conformational entropy can significantly influence the thermodynamics of the interaction of small molecule ligands with proteins. Therefore, we will examine this and related issues in the context of the ser/thr kinase p38¿. p38¿ is intimately associated with a variety of disease states, including cancer and neurological diseases, and is an active target for pharmaceutical development. Experiments are proposed to examine the changes in fast internal motion in this protein upon interaction with both natural and pharmacological small molecule ligands. Advanced NMR relaxation methods will be employed to measure main chain and side chain motion. A variety of analytical strategies will be used to gain insight into the quantitative contributions to the thermodynamics of complex formation and to discover their structural origins. In addition, the dynamical effects of regulatory protein bindng will also be examined. These data will go to the heart of the physical mechanism for activation and deactivation of this critical kinase by both natural effector proteins and man-made molecules. Complementary hydrogen exchange studies will also be carried out with the goal of exposing cooperative interactions within p38¿. This view will be particularly informative with respect to the emerging class of pseudo-allosteric drugs. A novel NMR-based approach using high-pressure perturbation and rapid three dimensional radial sampling will be employed to overcome limitations in the standard "native state" hydrogen exchange method in the context of large proteins, such as p38¿. Overall, the proposal rests on a significant foundation of preliminary results including an unusually deep and robust library of resonance assignments for a ser/thr kinase.
描述(由适用提供):高亲和力蛋白复合物对于大量复杂的调节过程至关重要。它们的形成涉及多样和复杂的复杂相互作用。这种复杂性反映在仅使用分子结构来计算蛋白质之间相互作用的能量学的困难中。实际上,该障碍极大地阻碍了药品的基于结构的设计。了解蛋白质与天然和药物配体的相互作用的能量和动态的基本起源显然对于优化“理性”药物设计的优化至关重要。核磁共振(NMR)弛豫方法的最新进展已使蛋白质会议状态之间的运动度量作为会议熵的代理。现在,最近的研究使用这种方法有很大的指示,即构象熵的变化可以显着影响小分子配体与蛋白质相互作用的热力学。因此,我们将在Ser/Thr激酶p38 p38的背景下检查这个问题和相关问题。 p38与包括癌症和神经疾病在内的多种疾病状态密切相关,并且是药物发育的积极靶标。提出了实验,以检查与天然和药物小分子配体相互作用后,该蛋白质中快速内运动的变化。将采用先进的NMR松弛方法来测量主链和侧链运动。各种分析策略将用于洞悉对复杂形成的热力学的定量贡献并发现其结构起源。另外,还将检查调节蛋白结合的动态效应。这些数据将是通过天然效应蛋白和人造分子激活和失活物理机制的核心。还将进行互补的氢交换研究,目的是揭示p38?内的合作相互作用。对于新兴的伪氧化药物类别,这种观点将特别有用。在大型蛋白质的背景下,将采用一种基于NMR的新型方法,使用高压扰动和快速的三维径向抽样来克服标准的“天然状态”氢交换方法的局限性,例如p38 p38,总体上,该提案取决于预先效果的重要基础,包括一个非常深入且稳健的seronance库,用于ser/ser/ser/ser/ser/ser/ser/ser/ser/ser/ser/ser/kin kin kin kin ser/ser/ser/ser/ser-sermance。
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)
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Wolfgang Peti其他文献
Wolfgang Peti的其他文献
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{{ truncateString('Wolfgang Peti', 18)}}的其他基金
Serine/Threonine Phosphatases in Neurological Diseases
神经系统疾病中的丝氨酸/苏氨酸磷酸酶
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10583671 - 财政年份:2023
- 资助金额:
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Shared Tundra screening cryo-EM for New England
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10413473 - 财政年份:2022
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Mechanism and activity of beta-lactam resistant enzymes in E. faecium and E. faecalis
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- 批准号:
10624757 - 财政年份:2019
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Protein Phosphatase 1 Holoenzyme Formation and Subunit Exchange
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9985412 - 财政年份:2019
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Mechanism and activity of beta-lactam resistant enzymes in E. faecium and E. faecalis
屎肠球菌和粪肠球菌中β-内酰胺抗性酶的机制和活性
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10391315 - 财政年份:2019
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Mechanism and activity of beta-lactam resistant enzymes in E. faecium and E. faecalis
屎肠球菌和粪肠球菌β-内酰胺抗性酶的机制和活性
- 批准号:
9927573 - 财政年份:2019
- 资助金额:
$ 33.53万 - 项目类别:
Dynamics & energetics of p38a kinase regulation by ligands
动力学
- 批准号:
8608555 - 财政年份:2013
- 资助金额:
$ 33.53万 - 项目类别:
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