Dynamic allosteric communication within nonribosomal peptide synthetase cyclization domains
非核糖体肽合成酶环化域内的动态变构通讯
基本信息
- 批准号:10387089
- 负责人:
- 金额:$ 10.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-01 至 2024-02-29
- 项目状态:已结题
- 来源:
- 关键词:Active SitesAnabolismAntibioticsAntineoplastic AgentsArchitectureBacitracinBindingBinding SitesBiologicalBiological AssayBleomycinChemicalsCholeraCommunicationComplexComputing MethodologiesCrystallographyCyclizationDrug DesignEngineeringEnzymesEscherichia coliGene ActivationImmunosuppressive AgentsLigand BindingModificationMolecularMycobacterium tuberculosisNatural ProductsNuclear Magnetic ResonancePharmacologic SubstancePlagueProteinsRegulationResearchSirolimusStructureSystemTertiary Protein StructureTherapeuticTuberculosisUrinary tract infectionUropathogenic E. coliVibrio choleraeVirulenceYersinia pestisantitumor agentenzyme mechanismimprovedinterestintermolecular interactionmicrobialnovelpathogenpeptide synthaseresponse
项目摘要
Project Summary
Biological activity, ranging from gene activation to enzyme regulation, occurs through molecular
interactions, and its regulation can be described as a redistribution of intermolecular interactions
through chemical modifications or ligand binding. Unfortunately, when a protein interacts with
two partners through remote binding sites, molecular mechanisms that would explain how
changes within proteins alter the communication between proteins are often elusive. This
challenge limits designing drugs that could alter interactions to rescue abnormal biological
activity. The conundrum also applies to microbial enzymatic factories called nonribosomal
peptide synthetases (NRPSs). NRPSs use contiguous protein domains to incorporate and
assemble simple substrates into complex products in an assembly line fashion. The products
are often valuable therapeutics, including antibiotics (bacitracin), antitumor agents
(bleomycin), and immunosuppressants (rapamycin), but others confer virulence to pathogens
(E. coli, V. cholerae, Y. pestis). NRPSs are the focus of much interest because engineering
them to incorporate different substrates could produce novel pharmaceuticals. However, like
assembly lines in factories, NRPSs are not static, and their domains interact transiently in a
dynamic architecture. Thus, understanding the molecular mechanisms of NRPSs, and
potentially engineering them, is tantamount to solving a dynamic, multi-dimensional puzzle.
Notably, it is unknown how substrates interact with some domains, and how these interactions,
in turn, promote communication between several partner domains, which is the situation we
described above for proteins. We found that structural dynamics within domains respond to
substrates to promote interactions between domains and that they couple remote binding sites
and enzymatic active sites. That is, dynamics contain keys to understanding both substrate
recognition and remote communication. This proposal aims to provide a molecular description of
the dynamics within critical NRPS domains and reveal its function in substrate and partner
domain recognition. We will use nuclear magnetic resonance, which can describe
experimentally dynamics at the atomic-level, to describe dynamic responses when domains
interact with each other, and with substrates as they do during synthesis. The studies are
supplemented with functional assays, computational methods, and crystallography, and will
answer longstanding questions about protein communication, enzyme mechanisms, and remote
communication within proteins. The results will provide a basis to engineer exogenous substrate
recognition into NRPSs, a condition for producing new pharmaceuticals through NRPS
reprogramming.
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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Dominique Pascal Frueh其他文献
Dominique Pascal Frueh的其他文献
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{{ truncateString('Dominique Pascal Frueh', 18)}}的其他基金
NMR studies of heterocyclization and epimerization in yersiniabactin synthesis
耶尔森菌素合成中杂环化和差向异构化的 NMR 研究
- 批准号:
8421252 - 财政年份:2013
- 资助金额:
$ 10.43万 - 项目类别:
NMR studies of heterocyclization and epimerization in yersiniabactin synthesis
耶尔森菌素合成中杂环化和差向异构化的 NMR 研究
- 批准号:
8667485 - 财政年份:2013
- 资助金额:
$ 10.43万 - 项目类别:
Dynamic allosteric communication within nonribosomal peptide synthetase cyclization domains
非核糖体肽合成酶环化域内的动态变构通讯
- 批准号:
10569523 - 财政年份:2013
- 资助金额:
$ 10.43万 - 项目类别:
Dynamic allosteric communication within nonribosomal peptide synthetase cyclization domains
非核糖体肽合成酶环化域内的动态变构通讯
- 批准号:
10358654 - 财政年份:2013
- 资助金额:
$ 10.43万 - 项目类别:
NMR studies of heterocyclization and epimerization in yersiniabactin synthesis
耶尔森菌素合成中杂环化和差向异构化的 NMR 研究
- 批准号:
9066739 - 财政年份:2013
- 资助金额:
$ 10.43万 - 项目类别:
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