Chemistry and energy transduction in kinesin motor proteins
驱动蛋白运动蛋白的化学和能量转导
基本信息
- 批准号:8876965
- 负责人:
- 金额:$ 4.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-01 至 2016-07-31
- 项目状态:已结题
- 来源:
- 关键词:ATP HydrolysisATP phosphohydrolaseActive SitesAddressAntineoplastic AgentsBindingBinding SitesBiochemicalBiochemical ReactionBiochemistryBiologicalBiological ModelsBiological ProcessBrainCardiacCatalysisCell physiologyChargeChemicalsChemistryChromosome SegregationClinicalComplexCouplingCrystallographyCytoskeletal ProteinsCytoskeletonDNADNA-Directed RNA PolymeraseDataDefectDevelopmentElementsEnzymesEventGTP-Binding ProteinsGenesGenetic TranscriptionGoalsHumanHuman BiologyHydrogen BondingIn VitroIndividualInfertilityInterruptionIsotopesKinesinKineticsKnowledgeLaboratoriesLeadLeftLinkLocationMalignant NeoplasmsMechanicsMedicalMicrotubulesMitosisMitotic ChromosomeModelingMolecularMolecular ConformationMotionMotorMovementMyopathyMyosin ATPaseNerve DegenerationNucleotidesOrganellesPhysiological ProcessesPolymersProtein ChemistryProteinsProtonsRNA HelicaseReactionRoleSeriesSiteStagingStructural ProteinSyndromeSystemTestingTherapeuticThermodynamicsTimeTransducersTransport VesiclesTubulinTumor SuppressionWaterWorkWritinganalogbasebiophysical propertiescancer cellcancer therapycell typecrosslinkdeprotonationdesigndriving forceinfrared spectroscopyinhibitor/antagonistinorganic phosphatemeltingnervous system disordernovelpolypeptideprotonationresearch studysmall molecule
项目摘要
DESCRIPTION (provided by applicant): Eukaryotic motor proteins utilize the cytoskeleton as roadways to transport a variety of intracellular cargo across relatively vast distances. The reaction of ATP with water to produce ADP and inorganic phosphate is the central and primary step in motor proteins that initiates critical cellular functions, including chromosome segregation during mitosis, gene replication, transcription, and transport of vesicles and organelles. These nanomotors all function by consuming this energy and coupling the chemical intermediates to a series of conformational changes that propel net celular motion. For kinesins, defects in this catalytic reaction and its chemo-mechanical transduction are linked to cancer, developmental errors, myopathies, and neurodegenerative conditions in humans. Although a complex sequence of intermediate states during ATP hydrolysis and mechanotransduction is predicted, only a small subset of states has been validated by direct structural observation. Thus, current empirical evidence of atomic-level interactions is not sufficient to assess the complete range of chemical steps in biological ATP hydrolysis and its partnered energy transduction. Recent data from our laboratories has captured key catalytic intermediates that resolve extant questions regarding mechanism and provide a new framework for further progress. Building upon these findings, our principal goal is to define novel roles for proton transfer and hydrogen bonding for ATP hydrolysis and chemo-mechanical coupling in the human Kinesin-5 protein, essential for mitosis and a target for cancer therapeutics. Questions to be tested are the identity of the chemical player in the first step of ATP hydrolysis, whether loops flanking the active site undergo conformational changes in the enzyme transition state, and if the central 2-sheet has a role in transducing information from the active site to other sites. The significance of the anticipated answers is twofold. As chemistry and motion are tautologically linked, this information is required to illuminate molecular mechanisms of motion in nanomotors, which are currently unclear from these deficits. Moreover, garnered experimental evidence will allow rational design of anti-cancer drugs directed against human Kinesin-5.
描述(由申请人提供):真核运动蛋白利用细胞骨架作为道路,在相对较远的距离内运输各种细胞内货物。ATP与水反应产生ADP和无机磷酸盐是运动蛋白的中心和初级步骤,它启动关键的细胞功能,包括有丝分裂过程中的染色体分离、基因复制、转录以及囊泡和细胞器的运输。这些纳米马达都是通过消耗这些能量,并将化学中间体耦合到一系列推动净细胞运动的构象变化中来发挥作用的。对于运动蛋白来说,这种催化反应及其化学机械转导中的缺陷与人类的癌症、发育错误、肌病和神经退行性疾病有关。虽然预测了ATP水解和机械转导过程中一系列复杂的中间状态,但只有一小部分状态通过直接结构观察得到了验证。因此,目前原子水平相互作用的经验证据不足以评估生物ATP水解及其相关能量转导的完整化学步骤。我们实验室最近的数据已经捕获了关键的催化中间体,解决了有关机制的现有问题,并为进一步的进展提供了新的框架。在这些发现的基础上,我们的主要目标是确定质子转移和氢键在ATP水解和化学-机械偶联中的新作用,人类激酶5蛋白是有丝分裂所必需的,也是癌症治疗的靶点。需要测试的问题是ATP水解第一步中的化学参与者的身份,活性位点两侧的环是否在酶过渡状态中发生构象变化,以及中心的2-sheet是否在将信息从活性位点转导到其他位点中起作用。预期答案的重要性是双重的。由于化学和运动是同义式地联系在一起的,因此需要这些信息来阐明纳米马达中运动的分子机制,这些机制目前尚不清楚。此外,获得的实验证据将允许合理设计针对人类运动蛋白-5的抗癌药物。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Sunyoung Kim其他文献
Sunyoung Kim的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Sunyoung Kim', 18)}}的其他基金
Chemistry and energy transduction in kinesin motor proteins
驱动蛋白运动蛋白的化学和能量转导
- 批准号:
8309148 - 财政年份:2011
- 资助金额:
$ 4.5万 - 项目类别:
Chemistry and energy transduction in kinesin motor proteins
驱动蛋白运动蛋白的化学和能量转导
- 批准号:
8520344 - 财政年份:2011
- 资助金额:
$ 4.5万 - 项目类别:
Chemistry and energy transduction in kinesin motor proteins
驱动蛋白运动蛋白的化学和能量转导
- 批准号:
8083837 - 财政年份:2011
- 资助金额:
$ 4.5万 - 项目类别:
Chemistry and energy transduction in kinesin motor proteins
驱动蛋白运动蛋白的化学和能量转导
- 批准号:
8774388 - 财政年份:2011
- 资助金额:
$ 4.5万 - 项目类别: