Role of Allostery in CAR Transactivation
变构在 CAR 反式激活中的作用
基本信息
- 批准号:9305482
- 负责人:
- 金额:$ 45.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-01 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressBilirubinBindingBinding SitesBiologicalBiological AssayBiological ProcessBiologyBiophysicsCellsComplexCrystallographyDNADNA BindingDNA SequenceDataDevelopmentDiseaseDistantEndocrineFamilyGene ExpressionGene Expression ProfileGenetic TranscriptionGenomic approachGoalsHormonalHumanIn VitroIndividualKnowledgeLaboratoriesLigand BindingLigandsLinkLiver neoplasmsMediatingMetabolicMinorModelingMolecularMolecular ConformationNuclear ReceptorsOutcomePathway interactionsPatternPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhysiologyPlayProteinsPsychological TechniquesRXRRecruitment ActivityReporter GenesResearch PersonnelResponse ElementsRoleSignaling MoleculeSiteSpecificityStimulusStructureStudentsSystemTechniquesTestingTheoretical StudiesToxinTransactivationX-Ray CrystallographyXenobioticsbasebiophysical analysisbiophysical propertiesbiophysical techniqueschromatin immunoprecipitationchromatin modificationcofactorconstitutive androstane receptorexperimental studyextracellulargenome-widein vivointerestknock-downlipophilicityliver developmentmouse modelnovelreceptorreceptor bindingreceptor functionresponsescaffoldskillssmall hairpin RNAsmall moleculethree dimensional structuretranscription factortranscriptome sequencing
项目摘要
Structure-Function Studies on CAR
The primary goal of this project is to determine the mechanisms of action of the
constitutive androstane receptor (CAR). CAR plays key roles in the clearance of
xenobiotics and endogenous toxins such as bilirubin. CAR belongs to the nuclear
receptor family of transcription factor proteins that mediate endocrine function
and play critical roles in development and physiology and pharmacology. The
functional activity of nuclear receptors is regulated by small molecular hormonal
and synthetic molecules. CAR is regulated by small-molecule signals. Earlier, we
produced preliminary evidence utilizing multiple biophysical and cell-based
assays to show how distinct allosteric pathways can fine-tune the activity of
nuclear receptors. Our goal here is to identify and distinguish between the
different allosteric pathways initiated by ligands, DNA and cofactors such as co-
activators and co-repressors. We will use a combination of crystallography and
biophysical techniques to determine the local and distant conformational changes
that occur upon ligand binding. With Dr. Tongye Shen we will use theoretical
techniques to predict allosteric pathways that can be further characterized by
experimental techniques. We will also use genomic approaches in colla boration
with Dr. Rachel Patton McCord to determine the role of allostery, in vivo. The
ultimate goal of this study is to develop our understanding of CAR and nuclear
receptors. Malfunctioning nuclear receptors are associated with several disease
states, and CAR activity has been associated with the development of liver
tumors in mouse models. In summary, we will address the following questions: (i)
What conformational pathways link ligand, DNA and coregulatory molecules? (ii)
How do these pathways regulate coactivator and DNA recognition? (iii) What is
the genome-scale impact of allostery in CAR? Thus, a detailed understanding of
these proteins, and CAR, will enable us to develop efficient therapies in the long
term.
轿车的结构-功能研究
这个项目的主要目标是确定
构成雄烷受体(CAR)。汽车在清理环境污染中起着关键作用
外源物质和内源性毒素,如胆红素。汽车属于核能
介导内分泌功能的转录因子受体家族蛋白
并在发育、生理学和药理学中发挥关键作用。这个
核受体的功能活性受小分子激素调节
和合成分子。CAR受到小分子信号的调节。此前,我们
利用多种生物物理和基于细胞的方法产生了初步证据
显示不同的变构途径可以微调活性的化验
核受体。我们在这里的目标是识别和区分
不同的变构途径由配体、DNA和辅因子等共同启动。
激活剂和共抑制物。我们将结合使用结晶学和
确定局部和远程构象变化的生物物理技术
发生在配基结合时。与沈同业博士一起,我们将用理论
预测变构途径的技术,可以进一步表征
实验技术。我们还将在Colla Boration中使用基因组方法
与雷切尔·巴顿·麦考德博士一起确定变构在体内的作用。这个
这项研究的最终目的是加深我们对汽车和核能的理解
感受器。核受体功能障碍与几种疾病有关
状态,CAR活动与肝脏的发育有关
小鼠模型中的肿瘤。综上所述,我们将解决以下问题:(I)
连接配体、DNA和共调节分子的构象途径是什么?(Ii)
这些途径是如何调节辅活化子和DNA识别的?(Iii)何谓
变构在CAR中的基因组规模影响?因此,详细了解
这些蛋白质和CAR将使我们能够长期开发有效的治疗方法
学期。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Allosteric pathways in nuclear receptors - Potential targets for drug design.
- DOI:10.1016/j.pharmthera.2017.10.014
- 发表时间:2018-03
- 期刊:
- 影响因子:13.5
- 作者:Fernandez EJ
- 通讯作者:Fernandez EJ
Effector-Binding-Directed Dimerization and Dynamic Communication between Allosteric Sites of Ribonucleotide Reductase.
效应器结合定向二聚化和核糖核苷酸还原酶变构位点之间的动态通讯。
- DOI:10.1021/acs.biochem.8b01131
- 发表时间:2019
- 期刊:
- 影响因子:2.9
- 作者:Pham,Bill;Lindsay,RichardJ;Shen,Tongye
- 通讯作者:Shen,Tongye
Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation.
- DOI:10.1016/j.bpc.2021.106552
- 发表时间:2021-04
- 期刊:
- 影响因子:3.8
- 作者:Lindsay RJ;Mansbach RA;Gnanakaran S;Shen T
- 通讯作者:Shen T
Regulatory Mechanics of Constitutive Androstane Receptors: Basal and Ligand-Directed Actions.
组成型雄甾烷受体的调节机制:基础和配体定向作用。
- DOI:10.1021/acs.jcim.9b00695
- 发表时间:2019
- 期刊:
- 影响因子:5.6
- 作者:Pham,Bill;Arons,AveryBancroft;Vincent,JeremyG;Fernandez,EliasJ;Shen,Tongye
- 通讯作者:Shen,Tongye
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