DYNAMICS OF GLUTATHIONE TRANSFERASES
DYNAMICS OF GLUTATHIONE TRANSFERASES
批准号:
6618100
负责人:
GORDON S. RULE
金额:
$22.17万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-08-01 至 2005-07-31
关键词:
X ray crystallography catalyst chemical kinetics computer simulation crystallization enzyme substrate complex glutathione transferase intermolecular interaction isozymes microcalorimetry model design /development molecular dynamics nuclear magnetic resonance spectroscopy physical model protein purification protein structure function site directed mutagenesis structural biology thermodynamics
中文摘要
描述(申请人提供):本研究的长期目标
程序是确定一种酶机制的分子基础
一类称为谷胱甘肽转移酶的酶。这些蛋白质形成了一个家族
解毒酶通过结合谷胱甘肽到广泛的
各种可能有害的疏水化合物。他们已经被证明
在肿瘤生长的启动过程中起着重要作用
化疗药物耐药性的发展。总而言之,这些
酶表现出非常广泛的底物特性。
这项提案的目标是确定
这些酶的分子动力学和酶功能。X射线衍生品
目前已知有六个类别的结构。尽管总体来说,
这些酶是相似的,每一类都有一个不同的分子
既影响底物专一性又影响酶的结构
机制。对于这些类中的三个类(α、Mu和pi),
确定了这些蛋白质的X-射线衍生化结构。在某些情况下,
这些结构表明酶的构象发生了相当大的变化。
到配基结合。在其他情况下,底物结合几乎不会引起
结构。因为所有这些研究都是在水晶中进行的
晶格,配体引起结构变化的程度和重要性
这些酶在溶液中的动力学尚不清楚。一个更全面的
对这些酶的了解将有助于开发更有用的
化疗药物。
这项建议的具体目的是研究底物诱导的变化。
用核磁共振研究人类类酶u、pi、α和theta的动态变化
光谱学。第一个要检验的假设是分子动力学
脊椎在这些酶的作用机制中起着重要作用。
酶通过门控底物的可获得性和产物的释放。动态感
存在和不存在时这些酶中主链原子的性质
不同的底物和产品的测量将通过测量
酰胺交换动力学、剩余偶极偶联、化学交换和15N
核松弛。需要检验的第二个假设是,动态
侧链残基的性质在分子识别中起着重要作用
不同的底物由同一种酶。野生型和野生型的侧链动力学
突变的蛋白质将通过‘3C,2H和19F核旋来表征
放松一下。
英文摘要
DESCRIPTION (provided by applicant): The long range goal of this research
program is to determine the molecular basis of the enzymatic mechanism of a
class of enzymes called glutathione transferases. These proteins form a family
of detoxification enzymes that function by conjugating glutathione to a wide
variety of potentially harmful hydrophobic compounds. They have been shown to
play an important role in the initiation of tumor growth, as well as in the
development of resistance to chemotherapeutic drugs. Collectively, these
enzymes show a remarkably broad range of substrate specificities.
The goal of this proposal is to determine the relationship between the
molecular dynamics and enzyme function for these enzymes. The x-ray derived
structures of six classes are currently known. Although the overall fold of
these enzymes are similar, each class possesses a distinct molecular
architecture which affects both the substrate specificity as well as the enzyme
mechanism. For three of these classes (alpha, mu, and pi), a large number of
x-ray derived structures of these proteins have been determined. In some cases,
these structures show considerable change in the conformation of the enzyme due
to ligand binding. In other cases, substrate binding causes little change in
structure. Since all of these studies have been performed in the crystalline
lattice, the extent and importance of ligand induced changes on the structure
and dynamics of these enzymes in solution is unknown. A more comprehensive
understanding of these enzymes will be useful in the development of more useful
chemotherapeutics.
The specific aims of this proposal are to investigate substrate induced changes
in the dynamics of human class mu, pi, alpha, and theta enzymes by NMR
spectroscopy. The first hypothesis to be tested is that molecular dynamics of
the backbone plays an important role in the enzymatic mechanism of these
enzymes by gating substrate accessibility and product release. The dynamic
properties of the backbone atoms in these enzymes in the presence and absence
of various substrates and products will be investigated with measurements of
amide exchange kinetics, residual dipolar coupling, chemical exchange, and 15N
nuclear relaxation. The second hypothesis to be tested is that the dynamic
properties of side-chain residues play an important role in the recognition of
different substrates by the same enzyme. Side chain dynamics of wild-type and
mutant proteins will be characterized by '3C, 2H, and 19F nuclear spin
relaxation.
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依托单位:
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依托单位:
RNA BINDING DOMAIN OF RHO
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资助金额:$16.17万
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财政年份:1996
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负责人:GORDON S. RULE
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依托单位:
SUBSTRATE SPECIFICITY OF GLUTATHIONE TRANSFERASES
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资助金额:$11.09万
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依托单位:
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依托单位:
SUBSTRATE SPECIFICITY OF GLUTATHIONE TRANSFERASES
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财政年份:1994
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依托单位:
SUBSTRATE SPECIFICITY OF GLUTATHIONE TRANSFERASES
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财政年份:--
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负责人:GORDON S. RULE
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依托单位:
NMR STUDIES OF PROTEIN STRUCTURE
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批准号:3890400
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项目类别:
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资助金额:$0.0万
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财政年份:--
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负责人:GORDON S. RULE
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依托单位:
NMR STUDIES OF PROTEIN STRUCTURE
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资助金额:$0.0万
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财政年份:--
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负责人:GORDON S. RULE
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依托单位:
国内基金
海外基金
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批准号:22302187
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项目类别:青年科学基金项目
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资助金额:30万元
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批准年份:2023
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负责人:孙潇
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依托单位: