Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics
通过跟踪酰基载体蛋白结合和构象动力学进行功能性杂化天然产物合成
基本信息
- 批准号:10045624
- 负责人:
- 金额:$ 29.8万
- 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:2016-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:4&apos-phosphopantetheineActinobacteria classAcyl Carrier ProteinAffectAffinityAmino Acid SequenceAmino AcidsAnabolismAntibioticsAuthorshipBehaviorBindingBinding ProteinsBiological AssayBiologyCalorimetryChemicalsChemistryCollaborationsComplexCoupledCouplingCrystallographyEngineeringEnvironmentEnzyme InteractionEnzymesEscherichia coliEventFatty AcidsFoundationsFundingFutureGenesGoalsHybridsHydro-LyasesLeadLengthMethodologyMethodsModelingMolecularMolecular ConformationMotionNatural ProductsOutcomePaperPathway interactionsPharmacologic SubstancePlayProtein ConformationProteinsPublicationsPublishingRattusResearchResearch PersonnelResearch Project GrantsRoleRouteSiteSpecificityStructureStudy SubjectTrainingUnited States National Institutes of HealthWorkarmbasecollegecrosslinkdesignexperienceexperimental studyholo-(acyl-carrier-protein) synthaseinnovationinsightmicroorganismmutantnext generationnovelpolyketide synthaseprotein protein interactionprotein structure functionsedimentation velocitysmall moleculesuccesstemporal measurementtoolundergraduate researchundergraduate studentvibration
项目摘要
PROJECT SUMMARY
Microorganisms produce structurally diverse molecules, many of which have been successfully repurposed as
pharmaceutical agents. These molecules are manufactured by multi-enzyme assemblies, which rely on acyl
carrier proteins (ACPs) to modify and transfer chemical intermediates to a team of enzymatic partners.
Strategic redesign of natural enzyme assemblies presents an exciting possible route to produce new
antibiotics, but the success of any redesign approach hinges on a thorough understanding of what leads to
chemically productive ACP-enzyme interactions. The goal of this study is to gain a molecular-level
understanding of how ACPs interact with their molecular cargo and enzymatic partners.
In the previous funding period, our lab developed new spectrophotometric methodologies that enabled us to
unveil the fast and transient interactions between ACPs and their molecular cargo, as well as between ACPs
and two enzymatic partners: a ketosynthase (KS) and dehydratase (DH). These studies led to 7 papers with 40
Haverford College undergraduate students earning co-authorship. We now seek to leverage these major
advancements to understand the complex interplay between ACP sequence and molecular cargo identity in
directing the phenomenon called “chain sequestration,” which is thought to play a critical role in directing
biocatalysis. We will also study how chain sequestration effects ACP-KS binding affinity and obtain ACP-KS
crosslinked structures for subsequent molecular-level structural characterization.
Results from these studies will guide the future biosynthesis of novel small molecules with potential
pharmaceutical activity. The work will be executed in the context of independent undergraduate research
projects and course-based undergraduate research experiences (CUREs), thereby exposing ~60
undergraduate students to advanced research at the chemistry-biology interface.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Louise Karine Charkoudian其他文献
Louise Karine Charkoudian的其他文献
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{{ truncateString('Louise Karine Charkoudian', 18)}}的其他基金
Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics
通过跟踪酰基载体蛋白结合和构象动力学进行功能性杂化天然产物合成
- 批准号:
9171419 - 财政年份:2016
- 资助金额:
$ 29.8万 - 项目类别:
Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics
通过跟踪酰基载体蛋白结合和构象动力学进行功能性杂化天然产物合成
- 批准号:
10581893 - 财政年份:2016
- 资助金额:
$ 29.8万 - 项目类别:
Mechanistic analysis of 6-deoxyerythronolide B synthase
6-脱氧赤酮内酯B合酶的机理分析
- 批准号:
8131690 - 财政年份:2009
- 资助金额:
$ 29.8万 - 项目类别:
Mechanistic analysis of 6-deoxyerythronolide B synthase
6-脱氧赤酮内酯B合酶的机理分析
- 批准号:
7970932 - 财政年份:2009
- 资助金额:
$ 29.8万 - 项目类别:
Mechanistic analysis of 6-deoxyerythronolide B synthase
6-脱氧赤酮内酯B合酶的机理分析
- 批准号:
7803213 - 财政年份:2009
- 资助金额:
$ 29.8万 - 项目类别:
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7182516 - 财政年份:2005
- 资助金额:
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