Exploring the Dynamics of Prolyl-tRNA Synthetases: Towards Developing a Screening Method for Species-Specific Inhibitors
探索脯氨酰-tRNA 合成酶的动力学:开发物种特异性抑制剂的筛选方法
基本信息
- 批准号:10797882
- 负责人:
- 金额:$ 9.99万
- 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:2016-02-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAmino Acid SequenceAmino Acyl-tRNA SynthetasesAnti-Infective AgentsArchitectureAtomic Force MicroscopyBindingBiochemistryBiological AssayCalorimetryCatalysisCellsChemicalsCouplingCrowdingDataDistantDockingDrug DesignDrug TargetingEducational process of instructingElectrostaticsEnvironmentEnzymatic BiochemistryEnzyme InteractionEnzyme KineticsEnzymesEquilibriumEquipmentEscherichia coliEventFamilyFluorescence SpectroscopyGrainIn VitroIndustrializationKineticsKnowledgeLabelLaboratoriesLigand BindingMeasurementMediatingMethodsModelingMolecularMolecular ConformationNMR SpectroscopyNatureNuclear Magnetic ResonanceOrganismPathogenicityPharmaceutical PreparationsPharmacologic SubstancePhysiologicalPlayPolymersProcessPropertyProtein BiosynthesisProtein ConformationProtein DynamicsProtein EngineeringProteinsQuantum MechanicsRadiolabeledReactionRegulationResearchResearch Project GrantsRoleSamplingShapesSiteSite-Directed MutagenesisSolventsStructureStudentsSystemTertiary Protein StructureThermodynamicsTitrationsUncertaintyVariantWorkabsorptionantimicrobial drugbiophysical chemistrydesigndrug developmentdrug discoveryenzyme modelenzyme structureexperienceexperimental studyflexibilityinhibitormembermolecular dynamicsmolecular mechanicsmolecular recognitionnovelpathogenproline-tRNAquantumscreeningside effectsimulationsmall molecule
项目摘要
Broadly speaking, our research group studies the interplay between enzyme dynamics and
catalysis. This supplemental proposal is developed to acquire Isothermal Titration Calorimeter,
which will aid in investigating the effects of molecular crowding on enzyme structure-dynamics-
functions. The interior of a cell is extremely crowded, which can potentially impact protein
properties such as structure, folding, stability, ligand binding, and enzyme catalysis. The crowding
effects could mediate through hard/steric/entropic and/or soft/chemical/enthalpic interactions. Our
objective is to investigate the exact mechanism of crowding/confinement and their impacts on
substrate binding and catalysis. We are studying the multidomain prolyl-tRNA synthetases
(ProRSs), which play a vital role in protein synthesis in all living organisms. Earlier, we
demonstrated that domain dynamics is central to ProRSs functions, which are impacted by the
crowder-induced shift in the conformational ensemble. Currently, the impact of the “uniform
crowding environment” (nonprotein-based crowders) and “structured crowding environment”
(protein-based crowders) on conformational dynamics and function of Escherichia coli (Ec) ProRS
is being probed. The mechanistic implications of crowding and confinement effects are significant
as these enzymes are promising anti-microbial drug targets. The conformational change and
crowder-enzyme interactions are being probed by fluorescence spectroscopy, molecular
dynamics simulations, and small molecule docking studies, while varying the size, shape,
chemical nature, and concentration of the crowders. We are examining the role of molecular
crowders on the substrate binding using Saturation Transfer Difference - Nuclear Magnetic
Resonance, which requires a large quantity of proteins and kinetics parameters are obtained from
enzyme kinetics assays using radiolabeled substrates. The isothermal titration calorimetry (ITC)
method is a label-free direct measurement of the heat evolved or absorbed during a binding event
between interacting molecules and enzyme-catalyzed reactions and requires less sample. ITC
experiments provide the thermodynamic profiles, which would enable us to establish the
molecular mechanism of crowding and confinement resulting in enzyme's altered function. A
detailed understanding of crowding effects on the properties of multidomain proteins like Ec
ProRS could open up new possibilities for protein designing and drug discovery. Moreover, the
ITC equipment would enable us to provide hands-on experiences to students in biochemistry and
biophysical chemistry courses (~25 students/semester) by designing course-embedded research
projects on calorimetry and teaching them the ligand binding thermodynamics in drug discovery.
一般来说,我们的研究小组研究酶动力学和
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Role of Oxidative Stress on SARS-CoV (SARS) and SARS-CoV-2 (COVID-19) Infection: A Review.
- DOI:10.1007/s10930-020-09935-8
- 发表时间:2020-12
- 期刊:
- 影响因子:0
- 作者:Suhail S;Zajac J;Fossum C;Lowater H;McCracken C;Severson N;Laatsch B;Narkiewicz-Jodko A;Johnson B;Liebau J;Bhattacharyya S;Hati S
- 通讯作者:Hati S
Cyclic Changes in Active Site Polarization and Dynamics Drive the 'Ping-pong' Kinetics in NRH:Quinone Oxidoreductase 2: An Insight from QM/MM Simulations.
- DOI:10.1021/acscatal.8b04193
- 发表时间:2018-11
- 期刊:
- 影响因子:12.9
- 作者:Clorice R. Reinhardt;Quin H. Hu;Caitlin G. Bresnahan;S. Hati;S. Bhattacharyya
- 通讯作者:Clorice R. Reinhardt;Quin H. Hu;Caitlin G. Bresnahan;S. Hati;S. Bhattacharyya
Editing Domain Motions Preorganize the Synthetic Active Site of Prolyl-tRNA Synthetase.
- DOI:10.1021/acscatal.0c02381
- 发表时间:2020-09-04
- 期刊:
- 影响因子:12.9
- 作者:Hu QH;Williams MT;Shulgina I;Fossum CJ;Weeks KM;Adams LM;Reinhardt CR;Musier-Forsyth K;Hati S;Bhattacharyya S
- 通讯作者:Bhattacharyya S
Evolution of Stronger SARS-CoV-2 Variants as Revealed Through the Lens of Molecular Dynamics Simulations.
- DOI:10.1007/s10930-022-10065-6
- 发表时间:2022-10
- 期刊:
- 影响因子:3
- 作者:Wozney, Alec J.;Smith, Macey A.;Abdrabbo, Mobeen;Birch, Cole M.;Cicigoi, Kelsey A.;Dolan, Connor C.;Gerzema, Audrey E. L.;Hansen, Abby;Henseler, Ethan J.;LaBerge, Ben;Leavens, Caterra M.;Le, Christine N.;Lindquist, Allison C.;Ludwig, Rikaela K.;O'Reilly, Maggie G.;Reynolds, Jacob H.;Sherman, Brandon A.;Sillman, Hunter W.;Smith, Michael A.;Snortheim, Marissa J.;Svaren, Levi M.;Vanderpas, Emily C.;Voon, Aidan;Wackett, Miles J.;Weiss, Moriah M.;Hati, Sanchita;Bhattacharyya, Sudeep
- 通讯作者:Bhattacharyya, Sudeep
Effects of Distal Mutations on Prolyl-Adenylate Formation of Escherichia coli Prolyl-tRNA Synthetase.
- DOI:10.1007/s10930-020-09910-3
- 发表时间:2020-10
- 期刊:
- 影响因子:0
- 作者:Zajac J;Anderson H;Adams L;Wangmo D;Suhail S;Almen A;Berns L;Coerber B;Dawson L;Hunger A;Jehn J;Johnson J;Plack N;Strasser S;Williams M;Bhattacharyya S;Hati S
- 通讯作者:Hati S
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Sudeep Bhattacharyay其他文献
Sudeep Bhattacharyay的其他文献
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{{ truncateString('Sudeep Bhattacharyay', 18)}}的其他基金
Exploring the Dynamics of Prolyl-tRNA Synthetases: Towards Developing a Screening Method for Species-Specific Inhibitors
探索脯氨酰-tRNA 合成酶的动力学:开发物种特异性抑制剂的筛选方法
- 批准号:
10203549 - 财政年份:2016
- 资助金额:
$ 9.99万 - 项目类别:
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