CHARACTERIZATION OF THE STRUCTURE AND DYNAMICS OF 16S RRNA A-SITE MUTANTS
16S RRNA A 位突变体的结构和动力学表征
基本信息
- 批准号:7598785
- 负责人:
- 金额:$ 0.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-03-01 至 2008-02-29
- 项目状态:已结题
- 来源:
- 关键词:Aminoglycoside AntibioticsAntibiotic ResistanceAntibioticsBacterial InfectionsBindingCell DeathCharacteristicsClassClinicalCodon NucleotidesComputer Retrieval of Information on Scientific Projects DatabaseDataDependenceDrug DesignElectrostaticsEukaryotaEukaryotic CellEvolutionFundingGenetic TranslationGrantInstitutionMessenger RNAMethodsMolecular ConformationMutationNucleotidesNumbersPharmaceutical PreparationsPlayPositioning AttributeProkaryotic CellsProteinsPublishingRationalizationResearchResearch PersonnelResistance developmentResourcesRibosomesRoentgen RaysRoleSiteSolutionsSourceSpecificityStructureSurfaceTestingTransfer RNATranslationsUnited States National Institutes of HealthWorkmutantnovelresistance mechanismsuccess
项目摘要
This subproject is one of many research subprojects utilizing the
resources provided by a Center grant funded by NIH/NCRR. The subproject and
investigator (PI) may have received primary funding from another NIH source,
and thus could be represented in other CRISP entries. The institution listed is
for the Center, which is not necessarily the institution for the investigator.
The 16S ribosomal A-site is directly involved in maintaining the fidelity of mRNA translation by the ribosome. The A-site is also the target of neamine-class aminoglycoside antibiotics. Binding of these antibiotics to the A-site reduces the level of fidelity in translation, resulting in non-functional protein products, resulting in cell death. Recent X-ray crystallographic evidence suggests the positions and contacts of nucleotides A1492 and A1493, within the A-site internal loop, play an important role in maintaining fidelity of mRNA translation. It has been shown that antibiotic binding to the A-site internal loop can distort its structure. The identity of position 1408, opposite to A1492 and A1493 within the A-site internal loop, largely controls the antibiotic binding specificity between Eukaryotes G1408 and Prokaryotes A1408, which is the main rationale behind the clinical success of these antibiotics in treating bacterial infections. In recent years a number of bacterial strains have developed resistance mechanisms to the neamine-class of antibiotics. One mechanism involves mutations in the sequence of the A-site target. Our hypothesis is that mutations of the 16S Ribosomal A-site must maintain a characteristic electrostatic surface for cognate recognition of the mRNA codon by the anti-codon loop of tRNA during translation. To test this hypothesis we are performing NMR studies to solve the solution-state structure for the prokaryotic and eukaryotic wild type A-site, along with several bacterial functional mutants generated in the lab of Dr. Phil Cunningham using his instant evolution methods. This work focuses on the sequence dependence of the A-site conformation and dynamics of positions A1492 and A1493. Binding studies and structure determination of a novel antibiotic, synthesized in the lab of Dr. Mark Spaller, bound to selected constructs are also being performed to explore new avenues in drug design. Comparing these structures to currently published data (NMR, x-ray, footprinting, etc.) will reveal structural and mechanistic aspects of drug binding, as well as provide rationalization of antibiotic resistance and mutant function.
该子项目是利用该技术的众多研究子项目之一
资源由 NIH/NCRR 资助的中心拨款提供。子项目及
研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金,
因此可以在其他 CRISP 条目中表示。列出的机构是
对于中心来说,它不一定是研究者的机构。
16S 核糖体 A 位点直接参与维持核糖体 mRNA 翻译的保真度。 A位点也是新胺类氨基糖苷类抗生素的作用靶点。 这些抗生素与 A 位点的结合会降低翻译的保真度,导致产生无功能的蛋白质产物,从而导致细胞死亡。 最近的 X 射线晶体学证据表明,A 位内环内核苷酸 A1492 和 A1493 的位置和接触在维持 mRNA 翻译保真度方面发挥着重要作用。 研究表明,抗生素与 A 位内环结合会扭曲其结构。位置1408与A位内环内的A1492和A1493相对,在很大程度上控制真核生物G1408和原核生物A1408之间的抗生素结合特异性,这是这些抗生素在治疗细菌感染方面临床成功的主要原因。 近年来,许多细菌菌株已经对新胺类抗生素产生了耐药机制。 一种机制涉及 A 位靶标序列的突变。 我们的假设是,16S 核糖体 A 位点的突变必须维持特有的静电表面,以便在翻译过程中 tRNA 的反密码子环对 mRNA 密码子进行同源识别。 为了检验这一假设,我们正在进行核磁共振研究,以解决原核和真核野生型 A 位点的溶液态结构,以及 Phil Cunningham 博士实验室使用他的即时进化方法产生的几种细菌功能突变体。 这项工作的重点是 A 位点构象的序列依赖性以及位置 A1492 和 A1493 的动力学。 Mark Spaller 博士实验室合成的新型抗生素与选定结构的结合研究和结构确定也在进行中,以探索药物设计的新途径。 将这些结构与当前发布的数据(NMR、X 射线、足迹等)进行比较将揭示药物结合的结构和机制方面,并提供抗生素耐药性和突变功能的合理化。
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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John SantaLucia其他文献
John SantaLucia的其他文献
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{{ truncateString('John SantaLucia', 18)}}的其他基金
Software for the accurate de novo 3D structure prediction of RNA
用于准确从头预测 RNA 3D 结构的软件
- 批准号:
8258224 - 财政年份:2010
- 资助金额:
$ 0.04万 - 项目类别:
Software for the accurate de novo 3D structure prediction of RNA
用于准确从头预测 RNA 3D 结构的软件
- 批准号:
8244020 - 财政年份:2010
- 资助金额:
$ 0.04万 - 项目类别:
Software for the accurate de novo 3D structure prediction of RNA
用于准确从头预测 RNA 3D 结构的软件
- 批准号:
8007200 - 财政年份:2010
- 资助金额:
$ 0.04万 - 项目类别:
TRAINING IN THE USE OF BRUKER AND VARIAN SPECTROMETERS AND NMR
布鲁克和瓦里安光谱仪和核磁共振的使用培训
- 批准号:
7598786 - 财政年份:2007
- 资助金额:
$ 0.04万 - 项目类别:
Software for Structural Bioinformatics of Nucleic Acid
核酸结构生物信息学软件
- 批准号:
7342843 - 财政年份:2005
- 资助金额:
$ 0.04万 - 项目类别:
Software for Structural Bioinformatics of Nucleic Acid
核酸结构生物信息学软件
- 批准号:
7123565 - 财政年份:2005
- 资助金额:
$ 0.04万 - 项目类别:
Software for Structural Bioinformatics of Nucleic Acid
核酸结构生物信息学软件
- 批准号:
7174714 - 财政年份:2005
- 资助金额:
$ 0.04万 - 项目类别:
Software for Structural Bioinformatics of Nucleic Acid
核酸结构生物信息学软件
- 批准号:
7010095 - 财政年份:2005
- 资助金额:
$ 0.04万 - 项目类别:
Software for Structural Bioinformatics of Nucleic Acid
核酸结构生物信息学软件
- 批准号:
6869920 - 财政年份:2005
- 资助金额:
$ 0.04万 - 项目类别:
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