Characterization of bacterial sensors using protein design
使用蛋白质设计表征细菌传感器
基本信息
- 批准号:9165148
- 负责人:
- 金额:$ 9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-22 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAmino AcidsAnti-Bacterial AgentsAntibiotic ResistanceAntibioticsApplications GrantsAreaAwardBacteriaBiological AssayBiologyBiophysicsCaliforniaCatalytic DomainCouplesCouplingCrystallizationCrystallographyDNADataDrug DesignDrug TargetingDrug resistanceEffectivenessEnvironmentEnzymesEquilibriumFaceFacultyFutureGene ExpressionGene ProteinsGoalsLaboratoriesLibrariesMapsMeasuresMembraneMentorsMethodsMicrofluidicsModificationMolecularMolecular ConformationPharmaceutical PreparationsPhasePhenotypePhosphoric Monoester HydrolasesPhosphotransferasesPopulationPredispositionPrincipal InvestigatorProkaryotic CellsProlinePropertyProtein EngineeringProteinsPublicationsReporterResearchResearch PersonnelResearch TrainingRoentgen RaysSan FranciscoScientistShapesSignal PathwaySignal TransductionStimulusStructureSystemTechnologyTemperatureTertiary Protein StructureTestingTrainingTransmembrane DomainUniversitiesVertebral columnVirulenceWorkX-Ray Crystallographyabstractingantimicrobialbacterial resistancebasecareercombinatorialconformational conversiondesigndimerexperienceflexibilityglobal healthnext generation sequencingprotein structure functionprotein-histidine kinaseresponsesensorskillssmall moleculesmall molecule inhibitor
项目摘要
Project Summary/Abstract
Two-component systems are major signaling pathways bacteria use to sense diverse stimuli such as
temperature, osmotic changes, and antibiotics and to initiate adaptive responses. In these systems the
histidine kinase (HK) detects the stimulus and relays the signal to its cognate response regulator, which alters
gene expression. As a postdoctoral scholar in Dr. William DeGrado's laboratory at the University of California,
San Francisco (UCSF), I have been designing protein constructs to study the structural and conformational
dynamics of HKs. Here, I propose to use an integrative experimental approach combining bacterial reporters,
enzymatic assays, x-ray structural studies, and droplet-based microfluidics technologies to understand how
conformational transitions in histidine kinases facilitate signal transduction. Recent HK structures suggest that
symmetry across the dimer interface is intricately related to catalytic state. The goal of this proposal is to
develop a molecular description of how structural signals induce symmetric to asymmetric conformational
transitions in the catalytic, cytoplasmic regions of HKs. I hypothesize that bistability of the dimer interface
`backbone' confers an essential conformational flexibility, which allows localized helical buckling to occur. The
consequence of this design is a transition from a continuous helical path along the backbone in the symmetric
state to a discontinuous path, which produces asymmetry. In Aim 1 I will examine how residue changes in the
buckling region of the backbone affects HK signaling. In Aim 2 I will use protein design to determine the
structural states associated with signaling in the cytoplasmic region of HKs. In Aim 3 I examine how signals
transmitted into the cytoplasmic region of HKs become modulated by coupling between effector domains and
the catalytic core. Completion of these aims will provide a molecular description of the structural and
conformational dynamics of HKs. A better understanding of the structural states and conformational changes
associated with signaling can inform structure-based design of small molecule inhibitors. By performing the
research in this proposal, I will increase my proficiency in protein design and biophysics while simultaneously
receiving strong training in X-ray crystallography, microfluidics, and high-throughput approaches to biology.
Expertise in these areas will better allow me to pursue my long-term scientific goals of using protein design as
a method to elucidate protein structure and function. The experience I will receive by working with my mentor
Dr. DeGrado and my collaborators during the K99 phase of the award will help me to become a stronger
scientist and better prepare me for a career as an independent researcher. The data and publications that
result from doing the work in this proposal will make me a stronger faculty candidate and help with future grant
applications. In general, completion of the research and training proposed in my application will provide me
with the skill set necessary for achieving my long-term career goal of becoming a principal investigator.
项目总结/文摘
项目成果
期刊论文数量(0)
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