ULTRAFAST TIME-RESOLVED CRYSTALLOGRAPHY ON SCAPHARCA DIMERIC AND TETRAMERIC H
ULTRAFAST TIME-RESOLVED CRYSTALLOGRAPHY ON SCAPHARCA DIMERIC AND TETRAMERIC H
批准号:
8171975
负责人:
WILLIAM E ROYER
金额:
$2.56万
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
项目状态:
已结题
起止时间:
2010-08-01 至 2011-07-31
关键词:
BackBindingBiological ModelsClamsComputer AnalysisComputer Retrieval of Information on Scientific Projects DatabaseCrystallographyDistalFundingGrantHemoglobinHistidineHumanInstitutionInvestigationKineticsLigandsOxygenPathway interactionsProteinsResearchResearch PersonnelResourcesRotationRouteSignal TransductionSolutionsSourceStructureTimeUnited States National Institutes of Healthmigrationmutantresearch studysuccesstime use
中文摘要
这个子项目是许多研究子项目中的一个
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来源获得主要资金,
因此可以在其他CRISP条目中表示。列出的机构是
中心,不一定是研究者的机构。
蛤,Scapharca inaequalivis,拥有两个血红蛋白,代表特殊的模型系统的研究蛋白质变构。 这两种血红蛋白结合氧合作使用的结构机制是非常不同的,从更好地研究人类血红蛋白。二聚血红蛋白,称为HbI,是具有两个相同亚基的变构的最简单的可能模型系统。 这种血红蛋白的时间分辨晶体学分析首次提供了真实的时间变构变化的初步结构描述(克纳普等人)。等人,2006,PNAS 103 7649-7654)。尽管这些实验总体上是成功的,但主要的缺点是晶体中非常高水平的成对再结合,这大大降低了变构转换期间的信号。我们对配体迁移的分析,包括时间分辨晶体学实验、溶液实验和计算分析(克纳普et al. 2009,Structure 17,in press),强烈表明晶格通过抑制通过远端组氨酸门退出所需的瞬时亚基旋转来限制配体退出。这些实验还揭示了通过“后门”渠道的潜在替代退出途径。我们正在制造突变体,它将允许配体在晶格的严格限制内通过这个后门离开。四聚体血红蛋白,称为HbII,由两个异二聚体形成,每个异二聚体具有与HbI相似的组装。两个不同亚基的存在将允许研究一个亚基如何影响第二个亚基,这在双重对称HbI中是不可能的。因此,我们建议使用时间分辨的X-射线衍射实验来阐明四聚体HbII和特定突变体HbII的动力学结构途径。
英文摘要
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.
The clam, Scapharca inaequivalvis, possesses two hemoglobins that represent exceptional model systems for the investigation of protein allostery. Both hemoglobins bind oxygen cooperatively using a structural mechanism that is very different from the more well studied human hemoglobin. The dimeric hemoglobin, termed HbI, is the simplest possible model system for allostery with two identical subunits. Time-resolved crystallographic analysis of this hemoglobin provided, for the first time, a preliminary structural description of allosteric changes in real time (Knapp et. al. 2006, PNAS 103 7649-7654). Despite the overall success of these experiments, a major drawback was the very high level of geminate rebinding in the crystal, which substantially reduced the signal during the allosteric transition. Our analysis of ligand migration, including time-resolved crystallographic experiments, solution experiments and computational analysis (Knapp et al. 2009, Structure 17, in press) strongly suggests the crystal lattice restricts ligand exit by damping transient subunit rotations that are required for exit through a distal histidine gate. These experiments also revealed a potential alternate exit route through a "back door" channel. We are producing mutants that will allow ligands to exit through this back door within the tight confines of the crystal lattice. The tetrameric hemoglobin, termed HbII, is formed from two heterodimers, each of which has a similar assembly to that of HbI. The presence of two different subunits will permit investigation of how one subunit impacts a second subunit, which is not possible in the two-fold symmetric HbI. Therefore, we propose to use time-resolved x-ray diffraction experiments to elucidate the kinetic structural pathway in the tetrameric HbII and specific mutants of HbII.
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