Role of Protein Dynamics in Modulating the Thermodynamic Linkages in Allostery
蛋白质动力学在调节变构热力学联系中的作用
基本信息
- 批准号:7367841
- 负责人:
- 金额:$ 28.59万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-03-01 至 2010-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlgorithmsAllosteric RegulationAmino Acid SequenceBe++ elementBerylliumBindingBinding SitesBiologicalComplement Factor BCoupledCyclic AMPCyclic AMP Receptor ProteinCyclic GMPCyclic NucleotidesDNA Binding DomainDataElementsEntropyFamilyHelix (Snails)Induced MutationKnowledgeLaboratory ResearchLeadLigand BindingLigandsLinkLiteratureMapsMass Spectrum AnalysisMeasurementModelingMotionMutagenesisMutationPatternPeptide Sequence DeterminationPlayProgress ReportsPropertyProtein DynamicsProteinsRangeResearchRoentgen RaysRoleSiteSolventsSpecificityStructureSucroseSystemTestingThermodynamicsTimeUreabaseear helixmutantphysical propertypolypeptideprotein structureprototypesuccesstranscription factor
项目摘要
cAMP receptor protein (CRP) is the prototype of a super-family of transcription factors. One key feature of
CRP's biological activity that has been the focus of this laboratory's research is the fundamental rules that
govern the allosteric activation by cAMP of its sequence-specific DMA binding. Recently we established, for
the first time in any allosteric system, that the energetics of allosteric parameters are linear functions of
protein dynamics. Using protein dynamics as the focus, there is a convergence among the results derived
from crystallographic, computational and functional energetic data. This preliminary success enables us to
focus our research effort on protein dynamics as the fundamental physical property to establish quantitative
linkages between CRP structure and mechanism(s) of allostery. For coming years we will address these
issues: 1. Is protein dynamics one of the fundamental properties of protein that modulate allostery? Two
strategies will be employed to test the validity of this relationship: a) loops which are solvent accessible are
targeted as structural elements to alter protein dynamics and allostery; b) Osmolytes, which affect dynamic
motions of proteins, will be employed as solvent additives to perturb protein dynamics and allostery.
2. Is there a network of structural elements that is particularly affected by allosteric regulation? The
structural elements the perturbation of which can lead to changes in protein dynamics and allostery will be
identified by: a) changes in the thermal B-factors in X-ray data due to mutation; b) H/D exchange
measurements coupled with mass spectrometry; and c) computation evidence for structural connectivity.
3. Can one use the knowledge gained in Aims 1 and 2 to assist in defining the structural elements
that exert long range effects in defining specificity of the activating effectors? CRP is activated most
efficiently by cAMP, although it can bind other cNMP without being activated. Literature results imply that
polypeptide outside of the cAMP binding site, specifically the DNA binding domain, dictates the ability of
CRP to respond to the bound ligand. Based on the preliminary computation results which show connectivity
between the cAMP binding site and the DNA binding domain, mutants will be used to test the connectivity
pattern. X-ray structural data of the cAMP binding domain will be used to test if the presence of the DNA
binding domain alters the structural connectivity pattern in the cAMP binding domain.
cAMP受体蛋白(CRP)是转录因子超家族的原型。的一个关键特征
CRP的生物活性一直是本实验室研究的重点,其基本规律是,
控制cAMP对其序列特异性DMA结合的变构激活。最近我们建立了,
在任何变构系统中第一次发现变构参数的能量是的线性函数
蛋白质动力学以蛋白质动力学为焦点,所得结果之间存在收敛性
从晶体学计算和功能的能量数据。这一初步成功使我们能够
将我们的研究工作集中在蛋白质动力学上,作为建立定量的蛋白质动力学的基本物理特性。
CRP结构和变构机制之间的联系。未来几年我们将解决这些问题
问题:1.蛋白质动力学是调节变构的蛋白质的基本性质之一吗?两
策略将被用来测试这种关系的有效性:a)溶剂可及的回路是
作为结构元件靶向改变蛋白质动力学和变构; B)渗透剂,其影响动力学
蛋白质的运动,将被用作溶剂添加剂来扰乱蛋白质动力学和变构。
2.是否存在一个特别受变构调节影响的结构元件网络?的
结构元素,其扰动可导致蛋白质动力学和变构的变化,
通过以下方式确定:a)由于突变导致X射线数据中热B因子的变化; B)H/D交换
与质谱联用的测量;和c)结构连接性的计算证据。
3.能否利用在目标1和2中获得的知识来帮助确定结构要素
在确定激活效应物的特异性方面发挥长距离作用?CRP最活跃
它可以被cAMP有效地结合,尽管它可以在不被激活的情况下结合其他cNMP。文献结果表明,
cAMP结合位点外的多肽,特别是DNA结合结构域,决定了
CRP对结合配体的反应。根据初步计算结果表明,
在cAMP结合位点和DNA结合结构域之间,突变体将用于测试连接性
格局cAMP结合结构域的X射线结构数据将用于测试DNA结合结构域是否存在。
结合结构域改变cAMP结合结构域中的结构连接模式。
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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JAMES C LEE其他文献
JAMES C LEE的其他文献
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{{ truncateString('JAMES C LEE', 18)}}的其他基金
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