STRUCTURAL ANALYSIS OF THE HGPRT FROM TRYPANOSOMA CRUZI
克氏锥虫 HGPRT 的结构分析
基本信息
- 批准号:2004412
- 负责人:
- 金额:$ 9.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-04-01 至 2002-03-31
- 项目状态:已结题
- 来源:
- 关键词:Trypanosoma cruzi X ray crystallography antiprotozoal agents binding proteins chemical structure function conformation drug design /synthesis /production drug screening /evaluation enzyme inhibitors enzyme structure enzyme substrate hypoxanthine phosphoribosyltransferase oligonucleotides parasitic disease chemotherapy site directed mutagenesis spectrometry synthetic enzyme trypanosomiasis
项目摘要
A purine salvage enzyme, hypoxanthine guanine phosphoribosyltransferase
(HGPRT), has been identified as a potential targets of drugs for the
treatment of a number f diseases cause by parasites, including Chagas'
disease. Described herein in a structure-based approach to the discovery
of potent inhibitors of HGPRT from Trypanosoma cruzi. Most of the
compounds currently being studied that target the HGPRT's of parasites act
as "subversive substrates" that are converted by the enzyme into modified
nucleotides that block subsequent enzymes, rather than directly inhibiting
the activity of the HGPRT itself. For this study, the focus will be on the
structural analysis of the trypanosomal enzyme and interactions with
inhibitors, rather than subversive substrates.
The most potent types of inhibitors of enzymes often are mimics of the
predicted transition state of the reaction. Using recombinant enzyme
produced in bacteria, the 3-D structure of the trypanosomal HGPRT will be
determined by X-ray crystallography. The initial structure will be in
conformation with a product analog bound to the active site provide direct
comparisons with the currently available structure of the human enzyme
bound to product, GMP. Several approaches will subsequently be employed
to provide information relevant to the transition state of the enzyme.
Site-directed mutagenesis of the cloned gene will be used to create mutant
enzymes that may be able to bind both substrates but may be incapable of
catalysis. These mutants will be used to co-crystallize the enzyme with
both natural substrates bound. A complimentary strategy will employ a
nonsalvageable purine analog (in which the reactive nitrogen is replaced
with a carbon atom) in co-crystallization experiments with the trypanosomal
enzyme and the second substrate, phosphoribosylphyrophospate. Also
cocrystallization experiments with the recombinant enzyme will be performed
using currently available transition state analogs. In addition to the
structural studies, the mechanism for the enzyme catalyzed reaction will
be investigate using steady state kinetics. These studies will provide
details with regard to relative reaction rates., Km 's, substrate binding
order and apparent K i's for inhibitors.
The structural and kinetic experiments proposed herein for the
trypansosomal HGPRT will contribute valuable information for the design of
potent inhibitors specifically targeted to this enzyme. In addition, the
elucidation of structural changes during substrate bind and catalysis will
assist inhibitor design efforts targeting the HGPRT's of other parasites
and will provide new information to increase our general knowledge about
enzyme catalysis and structure/function relationships.
嘌呤回收酶,次黄嘌呤鸟嘌呤磷酸核糖基转移酶
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
ANN E EAKIN其他文献
ANN E EAKIN的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('ANN E EAKIN', 18)}}的其他基金
MUTATIONAL ANALYSIS OF A PARASITE PURINE SALVAGE ENZYME
寄生虫嘌呤挽救酶的突变分析
- 批准号:
2833990 - 财政年份:1999
- 资助金额:
$ 9.33万 - 项目类别:
STRUCTURAL ANALYSIS OF THE HGPRT FROM TRYPANOSOMA CRUZI
克氏锥虫 HGPRT 的结构分析
- 批准号:
2887088 - 财政年份:1997
- 资助金额:
$ 9.33万 - 项目类别:
STRUCTURAL ANALYSIS OF THE HGPRT FROM TRYPANOSOMA CRUZI
克氏锥虫 HGPRT 的结构分析
- 批准号:
6373498 - 财政年份:1997
- 资助金额:
$ 9.33万 - 项目类别:
STRUCTURAL ANALYSIS OF THE HGPRT FROM TRYPANOSOMA CRUZI
克氏锥虫 HGPRT 的结构分析
- 批准号:
6169305 - 财政年份:1997
- 资助金额:
$ 9.33万 - 项目类别:
STRUCTURAL ANALYSIS OF THE HGPRT FROM TRYPANOSOMA CRUZI
克氏锥虫 HGPRT 的结构分析
- 批准号:
2672626 - 财政年份:1997
- 资助金额:
$ 9.33万 - 项目类别:
相似海外基金
CHEMICAL SCREENING AND OPTIMIZATION FACILITY - PROTEIN EXPRESSION AND/OR X-RAY CRYSTALLOGRAPHY
化学筛选和优化设施 - 蛋白质表达和/或 X 射线晶体学
- 批准号:
10942884 - 财政年份:2023
- 资助金额:
$ 9.33万 - 项目类别:
Taking Snapshots of Enzymatic Reactions Using X-ray Crystallography and Spectroscopy
使用 X 射线晶体学和光谱学拍摄酶反应快照
- 批准号:
10623717 - 财政年份:2023
- 资助金额:
$ 9.33万 - 项目类别:
EAGER: JOINT CRYO NEUTRON/X-RAY CRYSTALLOGRAPHY OF RNA AND RNA-PROTEIN INTERACTIONS
EAGER:RNA 和 RNA-蛋白质相互作用的联合冷冻中子/X 射线晶体学
- 批准号:
2224897 - 财政年份:2022
- 资助金额:
$ 9.33万 - 项目类别:
Standard Grant
Protein structure-based enhancement of enzyme performance for food and bioproduct applications using X-ray crystallography, protein modification and metabolic engineering methods
使用 X 射线晶体学、蛋白质修饰和代谢工程方法,基于蛋白质结构增强食品和生物产品应用中的酶性能
- 批准号:
RGPIN-2016-06209 - 财政年份:2021
- 资助金额:
$ 9.33万 - 项目类别:
Discovery Grants Program - Individual
Time-Resolved X-ray Crystallography of Dynamics in Cysteine-Dependent Enzymes
半胱氨酸依赖性酶动力学的时间分辨 X 射线晶体学
- 批准号:
10684770 - 财政年份:2020
- 资助金额:
$ 9.33万 - 项目类别:
Time-Resolved X-ray Crystallography of Dynamics in Cysteine-Dependent Enzymes
半胱氨酸依赖性酶动力学的时间分辨 X 射线晶体学
- 批准号:
10259757 - 财政年份:2020
- 资助金额:
$ 9.33万 - 项目类别:
Elucidating the Hidden Steps of Replicative DNA Synthesis by Time-Resolved X-ray Crystallography
通过时间分辨 X 射线晶体学阐明复制 DNA 合成的隐藏步骤
- 批准号:
2001434 - 财政年份:2020
- 资助金额:
$ 9.33万 - 项目类别:
Standard Grant
Time-Resolved X-ray Crystallography of Dynamics in Cysteine-Dependent Enzymes
半胱氨酸依赖性酶动力学的时间分辨 X 射线晶体学
- 批准号:
10099548 - 财政年份:2020
- 资助金额:
$ 9.33万 - 项目类别:
Optimizing protein expression for X-ray crystallography studies and medicinal chemistry
优化 X 射线晶体学研究和药物化学的蛋白质表达
- 批准号:
552236-2020 - 财政年份:2020
- 资助金额:
$ 9.33万 - 项目类别:
University Undergraduate Student Research Awards
Protein structure-based enhancement of enzyme performance for food and bioproduct applications using X-ray crystallography, protein modification and metabolic engineering methods
使用 X 射线晶体学、蛋白质修饰和代谢工程方法,基于蛋白质结构增强食品和生物产品应用中的酶性能
- 批准号:
RGPIN-2016-06209 - 财政年份:2020
- 资助金额:
$ 9.33万 - 项目类别:
Discovery Grants Program - Individual