CHARACTERIZATION OF MOLECULAR WIRES BOUND TO P450CAM, CCP, AND INOS
与 P450CAM、CCP 和 INOS 结合的分子线的表征
基本信息
- 批准号:8170093
- 负责人:
- 金额:$ 0.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-05-01 至 2011-02-28
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAffinityAutomobile DrivingBehaviorBindingCamphor 5-MonooxygenaseComputer Retrieval of Information on Scientific Projects DatabaseCytochromesDataElectron TransportElectronsEnzymesFundingGrantHemeInjection of therapeutic agentInstitutionLibrariesMolecularMolecular EvolutionOxidation-ReductionPathway interactionsPeptidesPeroxidasesProteinsPterinsResearchResearch PersonnelResourcesSeriesSiteSourceStructureSubstrate SpecificityUnited States National Institutes of HealthVariantWithdrawalanalogbasecofactordesignhuman NOS2A proteinmutantnovelnovel strategiesoxidationprogramssuccess
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
As part of an NIH funded project, we are developing the use of synthetic ?molecular wires?, substrate analogs tethered to photo-sensitizers or affinity tags, for the study of several heme enzymes including cytochrome P450s, peroxidases, and inducible nitric oxide synthase (iNOS). These wires are being designed to bind specifically to the active site of the target enzyme. Once bound, these structures may be used to photochemically trigger the injection or withdrawal of electrons from the redox active heme cofactor to allow the mechanism and turnover to be triggered in a novel way. In addition, these tethered substrate analogs may be used to select for differential binding behavior from a library of mutant proteins, allowing a new approach to the molecular evolution of novel substrate specificity. Crucial to the success of this program, and one of its key features, is the structural characterization of these artificial wires bound to their targets. In preliminary studies, we have been successful in obtaining structures of a series of synthetic wire variants bound to the active site of P450cam. This includes variations in the substrate, linker and sensitizer portion of the wire, and these structures have proven invaluable in driving our efforts to evolve P450s for novel substrate oxidation. We have also obtained a preliminary structure of a peptide based molecular wire bound to an electron transfer channel mutant of CcP, which demonstrates that we will be able to replace the electron transfer pathway in the enzyme with synthetic structures. Finally, we have recently obtained data on iNOS crystals grown in the presence of synthetic pterin based wires that show evidence of binding at the pterin site of the enzyme. We propose to extend these initial efforts by determining structures of a larger array of wires bound to WT and mutant forms of these three enzymes.
该子项目是利用
由NIH/NCRR资助的中心赠款提供的资源。子项目和
研究者(PI)可能从另一个NIH来源获得了主要资金,
因此可以在其他CRISP条目中表示。所列机构为
研究中心,而研究中心不一定是研究者所在的机构。
作为NIH资助项目的一部分,我们正在开发合成?分子线?与光敏剂或亲和标签相连的底物类似物,用于研究几种血红素酶,包括细胞色素P450、过氧化物酶和诱导型一氧化氮合酶(iNOS)。这些电线被设计为特异性结合到目标酶的活性位点。一旦结合,这些结构可以用于光化学触发电子从氧化还原活性血红素辅因子的注入或撤回,以允许以新的方式触发机制和周转。此外,这些拴系的底物类似物可用于从突变蛋白质文库中选择差异结合行为,从而为新型底物特异性的分子进化提供了新的方法。该计划成功的关键,也是其关键特征之一,是这些与目标结合的人造线的结构特征。在初步的研究中,我们已经成功地获得了一系列的合成线变体结合到P450 cam的活性位点的结构。这包括衬底,连接器和敏化剂部分的线的变化,这些结构已被证明是无价的,在推动我们的努力,以发展P450的新的衬底氧化。我们还获得了一个初步的结构的肽为基础的分子线绑定到电子转移通道突变体的CcP,这表明,我们将能够取代电子转移途径的酶与合成结构。最后,我们最近获得的数据iNOS晶体生长在合成的蝶呤为基础的电线,显示在蝶呤网站的酶结合的证据。我们建议通过确定与WT和这三种酶的突变形式结合的更大阵列的电线的结构来扩展这些初步的努力。
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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DAVID B. GOODIN其他文献
DAVID B. GOODIN的其他文献
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{{ truncateString('DAVID B. GOODIN', 18)}}的其他基金
CHARACTERIZATION OF MOLECULAR WIRES BOUND TO P450CAM, CCP, AND INOS
与 P450CAM、CCP 和 INOS 结合的分子线的表征
- 批准号:
8362151 - 财政年份:2011
- 资助金额:
$ 0.51万 - 项目类别:
CHARACTERIZATION OF MOLECULAR WIRES BOUND TO P450CAM, CCP, AND INOS
与 P450CAM、CCP 和 INOS 结合的分子线的表征
- 批准号:
7954420 - 财政年份:2009
- 资助金额:
$ 0.51万 - 项目类别:
CHARACTERIZATION OF MOLECULAR WIRES BOUND TO P450CAM, CCP, AND INOS
与 P450CAM、CCP 和 INOS 结合的分子线的表征
- 批准号:
7722111 - 财政年份:2008
- 资助金额:
$ 0.51万 - 项目类别:
HIGH RESOLUTION SAR STUDIES ON CAVITY MUTANTS OF CYTOCHROME C PEROXIDASE
细胞色素C过氧化物酶空腔突变体的高分辨率SAR研究
- 批准号:
7370386 - 财政年份:2006
- 资助金额:
$ 0.51万 - 项目类别:
HIGH RESOLUTION CRYSTALLOGRAPHY OF HEME ENZYMES WITH SUBSTRATE-LINKED SENSITIZER
具有底物连接敏化剂的血红素酶的高分辨率晶体学
- 批准号:
7370385 - 财政年份:2006
- 资助金额:
$ 0.51万 - 项目类别:
HIGH RES SAR OF CAVITY MUTANTS OF CYTOCHROME C PEROXIDAS
细胞色素 C 过氧化物空腔突变体的高分辨率 SAR
- 批准号:
6976274 - 财政年份:2004
- 资助金额:
$ 0.51万 - 项目类别:
Redox-Active and Luminescent Probes for Heme Enzymes
用于血红素酶的氧化还原活性和发光探针
- 批准号:
6940828 - 财政年份:2004
- 资助金额:
$ 0.51万 - 项目类别:
Redox-Active and Luminescent Probes for Heme Enzymes
用于血红素酶的氧化还原活性和发光探针
- 批准号:
6764840 - 财政年份:2004
- 资助金额:
$ 0.51万 - 项目类别:
Redox-Active and Luminescent Probes for Heme Enzymes
用于血红素酶的氧化还原活性和发光探针
- 批准号:
7119204 - 财政年份:2004
- 资助金额:
$ 0.51万 - 项目类别:
Redox-Active and Luminescent Probes for Heme Enzymes
用于血红素酶的氧化还原活性和发光探针
- 批准号:
7277225 - 财政年份:2004
- 资助金额:
$ 0.51万 - 项目类别:
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