Regulation of and Target Recognition by Protein Arginine Methyltransferase 1 (PRMT1)
Regulation of and Target Recognition by Protein Arginine Methyltransferase 1 (PRMT1)
批准号:
10653465
负责人:
JOAN M HEVEL
金额:
$41.37万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-05-01 至 2026-04-30
关键词:
Active SitesAdenosineAffectAreaArginineBindingBiochemicalBiochemistryBiologicalBiomedical ResearchCardiovascular DiseasesCardiovascular PathologyCatalysisCell Culture TechniquesCell Cycle RegulationCell ExtractsCell physiologyCellsChemistryChronic DiseaseCommunicationCysteineDNA RepairDevelopmentDiseaseDisease ProgressionEnzymesEstrogen ReceptorsEukaryotic CellEventExperimental DesignsFamilyFluorescenceFutureGoalsGroupingHealthHistone H4HistonesHomeostasisHumanIn VitroInflammatoryInterventionKidneyKidney DiseasesKineticsLungLung diseasesMammalian CellMediatingMediatorMedicineMethylationModificationN,N-dimethylarginineNerve DegenerationNeurodegenerative DisordersOxidative StressPharmaceutical PreparationsPharmacologic SubstancePlayPost-Translational Protein ProcessingProgesterone ReceptorsProtein DynamicsProtein InhibitionProtein IsoformsProtein MethylationProtein-Arginine N-MethyltransferaseProteinsRegulationResearchResearch PersonnelRoleSignal TransductionSiteSpecificitySpectrum AnalysisStressTestingTrainingTranscriptional RegulationTranslationsTreatment ProtocolsUnited States National Institutes of HealthUniversitiesUtahVariantViral PathogenesisWorkWritinganti-cancer therapeuticbiophysical techniquescarcinogenesiscareerchemical reactiondesigndimerdimethylargininedrug developmentepigenetic regulationexperimental analysisgraduate studentin vivoinhibitorinterestmolecular recognitionmonomernon-histone proteinnoveloxidationprogramsprotein functionsmall moleculesupportive environmenttherapeutic targettoolundergraduate researchundergraduate student
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Protein arginine methylation catalyzed by Protein arginine methyltransferase 1 (PRMT1) is of
intense current interest as an anti-cancer therapeutic target, as well as a mediator of lung, kidney,
neurodegenerative and cardiovascular pathologies. To date, the majority of studies
characterizing the consequences of PRMT1-mediated protein methylation have not considered
the biochemical mechanisms by which PRMT1 activity is altered, which is pivotal in understanding
how PRMT1 participates in cellular homeostasis, the progression of the aforementioned disease
states, and in developing treatment protocols to control PRMT1-dependent cellular events. The
two hypotheses being tested in this project are: 1) changes in oligomeric state and site-specific
cysteine oxidation of the PRMT1 protein affect substrate targeting and activity, and 2) that a
cysteine residue in PRMT1 can be harnessed to create/upgrade isoform-specific PRMT1
inhibitors. In Aim 1, novel fluorescence-based biophysical methods will be used to characterize
the dynamics of PRMT1 oligomer formation in intact cells. Strategically designed variants of
PRMT1 which present as tetramers, dimers, or monomers will be used to identify binding and
catalytic differences in the targeting by each oligomer, aiding in the ongoing effort to understand
molecular recognition rules of PRMT1 for its substrates. The effect of sulfenylation at a cysteine
residue near the active site of PRMT1 will also be characterized, allowing for the development of
stable oxidized and reduced mimics of PRMT1 to be used as research tools in areas of human
health affected by oxidative stress. The objectives in Aim 1 are built upon initial in vitro findings
by the PI and are expected to apply to the long-term goal of characterizing mechanisms of
regulating PRMT1 activity in vivo. In Aim 2, the strategy of using a nucleophilic cysteine near the
active site of PRMT1 to enable covalent inhibition by adenosine derivatives will be explored. This
strategy would be a valuable way to salvage inhibitors that show a lack of isoform-specificity, but
otherwise perform well to inhibit PRMT activity. Covalent inhibitors represent a novel, rationale
avenue for developing PRMT1 drugs and research tools. Undergraduate and graduate
researchers with interests in future careers in biomedical research or medicine will be involved in
the project and receive training in experimental design and analysis, notebook keeping, scientific
writing and presentation.
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依托单位:
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依托单位:
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