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(由申请人提供):本研究的长期目标
该计划是为了确定一个酶促机制的分子基础,
一类叫做谷胱甘肽转移酶的酶。这些蛋白质组成了一个家族
解毒酶的功能是将谷胱甘肽结合到广泛的
各种潜在有害的疏水化合物。刻意为
在肿瘤生长的起始中起重要作用,以及在
对化疗药物产生耐药性。总的来说,这些
酶显示出非常广泛的底物特异性。
本提案的目标是确定
这些酶的分子动力学和酶功能。X射线导出
目前已知六类结构。虽然整体折叠
这些酶是相似的,每一类都有不同的分子
影响底物特异性和酶的结构
机制对于其中的三个类(alpha、mu和pi),
已经确定了这些蛋白质的X射线衍生结构。在某些情况下,
这些结构显示出酶构象的相当大的变化,
与配体结合在其他情况下,底物结合引起的变化很小,
结构由于所有这些研究都是在晶体中进行的,
晶格,配体诱导结构变化的程度和重要性
并且这些酶在溶液中的动力学是未知的。更全面
了解这些酶将有助于开发更有用的
化疗药物
本提案的具体目的是研究底物诱导的变化
在人类mu、pi、alpha和theta类酶的动力学中,
谱第一个要检验的假设是,
骨架在这些酶的酶促机制中起重要作用,
酶通过门控底物可及性和产物释放。动态
这些酶中的骨架原子在存在和不存在下的性质
各种基板和产品将进行调查与测量
酰胺交换动力学、残余偶极偶联、化学交换和15N
核弛豫第二个要检验的假设是,
侧链残基的性质在识别
用同一种酶处理不同的底物。野生型的侧链动力学和
突变蛋白质的特征是13C、2H和19F核自旋
放松.
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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资助金额:$16.17万
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依托单位:
SUBSTRATE SPECIFICITY OF GLUTATHIONE TRANSFERASES
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依托单位:
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财政年份:1994
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依托单位:
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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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资助金额:$0.0万
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财政年份:--
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依托单位:
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资助金额:30万元
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负责人:孙潇
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依托单位: