Structural and Dynamic Mechanisms in Classical Protein Allostery
经典蛋白质变构的结构和动力学机制
基本信息
- 批准号:10372370
- 负责人:
- 金额:$ 7.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-20 至 2022-06-30
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAffectAllosteric RegulationBehaviorBindingBiochemicalBiologicalBiologyCell physiologyCharacteristicsChemistryChorismate MutaseCommunicationComputing MethodologiesDissectionDistalDistantDrug DesignEnzymesEventExhibitsFundingGoalsKnowledgeLabelLigand BindingLigandsMechanicsMetabolismMethodologyMolecular ConformationMonitorMovementNMR SpectroscopyParentsPathway interactionsPharmaceutical PreparationsProtein EngineeringProteinsRegulationResearchResolutionRoleSamplingSignal TransductionSiteStructureSystemWorkanalogbiophysical techniqueschemical synthesisconformational conversiondesigndimerdrug developmentnovelpromoterprotein structureresponsesmall molecule
项目摘要
Abstract (Parent R01 funded)
Allosteric regulation of protein activity is a physico-mechanical phenomenon that underlies the coordination of
cellular events throughout biology. Signal transduction, metabolism, and other essential cellular processes are
completely reliant on the executions of conformational and dynamic changes that enable allosteric proteins to
communicate between distant sites. To understand such biological mechanisms – and by extension to
understand how to rationally alter cellular processes, either with drugs or protein engineering – is to understand
this fundamental problem of how allosteric regulation works. Yet, even though allosteric regulation has been
recognized for decades and despite the recent realization that dynamics contributes to allostery, our
understanding of allosteric mechanism is still at a rudimentary level. One limitation has been that the roles of
dynamics in allostery have been drawn from just a few systems, most of which lack the classic indicators of
functional allostery. Another limitation is that gaining accurate information on functional dynamics is
experimentally challenging. To identify basic working principles of allostery, mechanisms of allosteric behavior
must be observed in proteins that are “strongly allosteric”, where allosteric movements and signatures will be
more easily identified. In the long term, knowledge of allosteric mechanism will enhance protein research in
general and have a huge positive impact on design of allosteric drugs and allosteric proteins. The focus of this
work will be on the allosteric enzyme chorismate mutase (CM). By all considerations, this enzyme appears to be
ideal for high-resolution dissective studies of its allosteric mechanisms. CM is a canonical allosteric enzyme as
evidenced by a number of characteristics: it is a symmetric dimer with active sites separated by 40 Å; it
undergoes T-to-R conformational transitions; it exhibits homotropic allostery (Hill coefficient = 1.6); and it exhibits
heterotropic allostery with small molecule effectors that modulate activity up (by Trp) or down (by Tyr). CM is 60
kDa which makes it amenable to solution NMR studies, and it is extremely soluble and durable and yields
outstanding quality NMR spectra. The rich allosteric characteristics of CM will allow classical allostery to be
examined experimentally using NMR and other biochemical and biophysical methods (including computations)
in unprecedented detail. In this proposal, Aims 1 and 2 employ NMR, computational methods, and chemical
synthesis to characterize the structural and dynamic features of apo and liganded states of CM in solution. The
responses of CM to binding effectors and a transition state analog will be monitored, all towards the goal of
identification of mechanisms of heterotropic long-range communication. Aim 3 is focused on extending a novel
labeling methodology for monitoring mechanisms of homotropic allostery. “Click” chemistry will be used to
covalently and specifically tether CM promoters together to stabilize samples used for studying the elusive singly
ligated state. This approach will be useful for NMR studies of protein dimers in general.
摘要(家长R01资助)
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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Andrew L Lee其他文献
Prostate Specific Antigen Doubling Time
前列腺特异性抗原倍增时间
- DOI:
- 发表时间:
2008 - 期刊:
- 影响因子:0
- 作者:
P. Arlen;F. Bianco;W. Dahut;A. D'Amico;W. Figg;S. Freedland;J. Gulley;P. Kantoff;M. Kattan;Andrew L Lee;M. Regan;O. Sartor - 通讯作者:
O. Sartor
Utility of the percentage of positive prostate biopsies in predicting PSA outcome after radiotherapy for patients with clinically localized prostate cancer.
前列腺活检阳性百分比在预测临床局限性前列腺癌患者放疗后 PSA 结果中的效用。
- DOI:
- 发表时间:
2003 - 期刊:
- 影响因子:0
- 作者:
U. Selek;Andrew L Lee;L. Levy;D. Kuban - 通讯作者:
D. Kuban
Andrew L Lee的其他文献
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{{ truncateString('Andrew L Lee', 18)}}的其他基金
Mechanisms and dynamics of allosteric function in proteins
蛋白质变构功能的机制和动力学
- 批准号:
10653812 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Mechanisms and dynamics of allosteric function in proteins
蛋白质变构功能的机制和动力学
- 批准号:
10338723 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Mechanisms and dynamics of allosteric function in proteins
蛋白质变构功能的机制和动力学
- 批准号:
10691713 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Request for a 500 MHz NMR console and nitrogen-cooled cryoprobe
请求 500 MHz NMR 控制台和氮冷冷冻探头
- 批准号:
10440662 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Equipment Supplement to Mechanisms and dynamics of allosteric function in proteins
蛋白质变构功能机制和动力学的设备补充
- 批准号:
10669454 - 财政年份:2022
- 资助金额:
$ 7.7万 - 项目类别:
Structural and Dynamic Mechanisms in Classical Protein Allostery
经典蛋白质变构的结构和动力学机制
- 批准号:
10021672 - 财政年份:2019
- 资助金额:
$ 7.7万 - 项目类别:
Structural and Dynamic Mechanisms in Classical Protein Allostery
经典蛋白质变构的结构和动力学机制
- 批准号:
10216306 - 财政年份:2019
- 资助金额:
$ 7.7万 - 项目类别:
Dynamic Networks and Mechanisms of Allosteric Communication in Proteins
蛋白质变构通讯的动态网络和机制
- 批准号:
7933132 - 财政年份:2009
- 资助金额:
$ 7.7万 - 项目类别:
The role of dynamics in enzyme mechanism and allostery
动力学在酶机制和变构中的作用
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9979900 - 财政年份:2008
- 资助金额:
$ 7.7万 - 项目类别:
Intra- and Intermolecular Dynamics of Dihydrofolate Reductase
二氢叶酸还原酶的分子内和分子间动力学
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7749030 - 财政年份:2008
- 资助金额:
$ 7.7万 - 项目类别:
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