Functional Characterization of FKBP52 Interactions with Steroid Hormone Receptors
FKBP52 与类固醇激素受体相互作用的功能表征
基本信息
- 批准号:8325101
- 负责人:
- 金额:$ 18.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-09-01 至 2013-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAffinityAffinity LabelsAndrogen ReceptorBindingBinding ProteinsBinding SitesBiological AssayChemosensitizationClientComplexCysteineDataDefectDevelopmentDiseaseFK506GleanGlucocorticoid ReceptorGoalsHormonesImmunophilinsKnockout MiceLeadLibrariesLigand Binding DomainLinkMalignant NeoplasmsMalignant neoplasm of prostateMammalian CellMammalsMass Spectrum AnalysisMediatingModelingMolecular ChaperonesMolecular ConformationMusMutationNaturePharmaceutical PreparationsPhenotypePhotoaffinity LabelsPhysiologicalPlayProgesterone ReceptorsProlineProteinsReceptor Mediated Signal TransductionRegulationReporterRoleSiteSpecificityStagingSteroid ReceptorsStructureSystemTacrolimus Binding ProteinsTestingTherapeuticYeastsaffinity labelingbasecrosslinkdesigndimerinhibitor/antagonistinsightknockout genemutantnovelreceptorreceptor functionreproductiveresearch studyresponsesmall moleculesteroid hormone receptortacrolimus binding protein 4therapeutic target
项目摘要
DESCRIPTION (provided by applicant): The Hsp90 binding protein FKBP52, through interactions with the steroid hormone receptors, plays important physiological and potentially pathological roles in mammals. FKBP52 specifically regulates the androgen, progesterone and glucocorticoid receptors. Thus, FKBP52 represents an attractive therapeutic target for the treatment of hormone-dependent cancers such as prostate cancer. We have made progress in understanding the regions of functional importance on FKBP52, but we still do not know where the FKBP52 interaction site is on the receptors. The main hypothesis to be tested in this proposal is that FKBP52 potentiation of receptor function occurs through direct contacts between the FKBP52 FK1 domain and the receptor ligand binding domain leading to an enhancement of hormone binding. The dynamic nature by which the receptors achieve their hormone bound conformations to which FKBP52 associates makes it impractical to use a simple purified protein system. Thus, we must use more sophisticated approaches to analyze direct interactions between the steroid receptors and associated cochaperones. Each of the specific aims detailed below are independent from each other, but are all aimed at proving the proposed interaction between the FKBP52 FK1 domain and the receptor LBD and targeting that interaction with small molecule inhibitors. The long term goal of this project is the development of novel drugs for the treatment of hormone-dependent cancers. Towards this goal our immediate specific aims are: Aim #1: Use a previously validated androgen receptor-mediated reporter assay in yeast to identify random mutations within the receptor that alter the receptor's response to the FKBP proteins. Aim #2: Use directed photo affinity labeling of a cysteine-lacking FKBP52 mutant in combination with cross linking/mass spectrometry to identify and characterize the FKBP52-receptor interaction site. Aim #3: Screen compound libraries for selective FKBP52 inhibitors and characterize the specificity of inhibition and FKBP52 binding sites. We have identified two selective FKBP52 inhibitors to date.
描述(由申请人提供):Hsp90结合蛋白FKBP52通过与类固醇激素受体的相互作用,在哺乳动物中发挥重要的生理和潜在的病理作用。FKBP52特异性调节雄激素、孕激素和糖皮质激素受体。因此,FKBP52是治疗激素依赖性癌症(如前列腺癌)的一个有吸引力的治疗靶点。我们在了解FKBP52的功能重要区域方面取得了进展,但我们仍然不知道FKBP52在受体上的相互作用位点在哪里。本研究要验证的主要假设是FKBP52受体功能的增强是通过FKBP52 FK1结构域与受体配体结合结构域的直接接触而发生的,从而导致激素结合的增强。受体实现与FKBP52结合的激素结合构象的动态性质使得使用简单的纯化蛋白系统变得不切实际。因此,我们必须使用更复杂的方法来分析类固醇受体和相关伴侣之间的直接相互作用。下面详细介绍的每一个具体目标都是相互独立的,但都旨在证明FKBP52 FK1结构域与受体LBD之间的相互作用,并针对这种相互作用与小分子抑制剂。该项目的长期目标是开发治疗激素依赖性癌症的新药。为了实现这一目标,我们的直接具体目标是:目标1:在酵母中使用先前验证的雄激素受体介导的报告基因试验来识别受体内的随机突变,这些突变会改变受体对FKBP蛋白的反应。目的#2:结合交联/质谱法,使用半胱氨酸缺失FKBP52突变体的定向光亲和标记来鉴定和表征FKBP52受体相互作用位点。目的#3:筛选选择性FKBP52抑制剂的化合物文库,并表征抑制和FKBP52结合位点的特异性。迄今为止,我们已经确定了两种选择性FKBP52抑制剂。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Androgen receptor splice variants are resistant to inhibitors of Hsp90 and FKBP52, which alter androgen receptor activity and expression.
- DOI:10.1016/j.steroids.2012.12.013
- 发表时间:2013-06
- 期刊:
- 影响因子:2.7
- 作者:Shafi AA;Cox MB;Weigel NL
- 通讯作者:Weigel NL
The FKBP52 Cochaperone Acts in Synergy with β-Catenin to Potentiate Androgen Receptor Signaling.
FKBP52联酮与β-catenin的协同作用可增强雄激素受体信号传导。
- DOI:10.1371/journal.pone.0134015
- 发表时间:2015
- 期刊:
- 影响因子:3.7
- 作者:Storer Samaniego C;Suh JH;Chattopadhyay A;Olivares K;Guy N;Sivils JC;Dey P;Yumoto F;Fletterick RJ;Strom AM;Gustafsson JÅ;Webb P;Cox MB
- 通讯作者:Cox MB
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Marc B Cox其他文献
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{{ truncateString('Marc B Cox', 18)}}的其他基金
Functional Characterization of FKBP52 Interactions with Steroid Hormone Receptors
FKBP52 与类固醇激素受体相互作用的功能表征
- 批准号:
7895986 - 财政年份:2009
- 资助金额:
$ 18.32万 - 项目类别:
Functional Characterization of FKBP52 Interactions with Steroid Hormone Receptors
FKBP52 与类固醇激素受体相互作用的功能表征
- 批准号:
7672264 - 财政年份:2008
- 资助金额:
$ 18.32万 - 项目类别:
Functional Characterization of FKBP52 Interactions with Steroid Hormone Receptors
FKBP52 与类固醇激素受体相互作用的功能表征
- 批准号:
8138498 - 财政年份:2008
- 资助金额:
$ 18.32万 - 项目类别:
Functional Characterization of FKBP52 Interactions with Steroid Hormone Receptors
FKBP52 与类固醇激素受体相互作用的功能表征
- 批准号:
7498086 - 财政年份:2008
- 资助金额:
$ 18.32万 - 项目类别:
Functional Characterization of FKBP52 Interactions with Steroid Hormone Receptors
FKBP52 与类固醇激素受体相互作用的功能表征
- 批准号:
7901370 - 财政年份:2008
- 资助金额:
$ 18.32万 - 项目类别:
Physiological Roles of Receptor-Associated Immunophilins
受体相关亲免素的生理作用
- 批准号:
7015565 - 财政年份:2005
- 资助金额:
$ 18.32万 - 项目类别:
Physiological Roles of Receptor-Associated Immunophilins
受体相关亲免素的生理作用
- 批准号:
6835062 - 财政年份:2005
- 资助金额:
$ 18.32万 - 项目类别:
Physiological Roles of Receptor-Associated Immunophilins
受体相关亲免素的生理作用
- 批准号:
7166079 - 财政年份:2005
- 资助金额:
$ 18.32万 - 项目类别:
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