THE ROLE OF PIN1 IN MITOSIS WITH DESIGNED INHIBITORS
PIN1 在有丝分裂中与设计抑制剂的作用
基本信息
- 批准号:6387319
- 负责人:
- 金额:$ 17.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2000
- 资助国家:美国
- 起止时间:2000-09-01 至 2003-08-31
- 项目状态:已结题
- 来源:
- 关键词:biological signal transduction cell cycle cell cycle proteins cell growth regulation conformation drug design /synthesis /production enzyme activity enzyme inhibitors enzyme mechanism enzyme substrate analog molecular chaperones peptidylprolyl isomerase phosphoprotein phosphatase phosphoserine proline protein folding
项目摘要
DESCRIPTION: Pin 1, a newly discovered regulator of mitosis signal
transduction, is an enzyme that acts on phosphoserine-proline amides. The
unique phosphorylation dependent peptidyl-prolyl isomerase activity of Pin1 in
regulating mitosis makes it a very attractive novel target for potential cancer
chemotherapeutics. Pin 1 is hypothesized to regulate mitosis by a
conformational switch, isomerizing key proline amides in a set of proteins that
are upregulated during mitosis. Cdc25 specifically is known to interact with
Pin1 through two phosphoserine-proline motifs. Cdc25 phosphatase regulates the
activity of the mitosis-specific kinase, Cdc2 complexed with cyclin B. Many
prolines require isomerization of the amide bond preceding proline between the
trans and cis conformations in order to fold into the biologically active
conformation. the folding process is accelerated by the peptidyl-prolyl
isomerase (PPIase enzymes). A better mechanistic understanding of the native
PPIase activity of the Pin 1 enzyme will give insight into PPIase-dependent
processes. The first Specific Aim concerns Pin1 inhibition by conformationally
constrained cis- and trans- proline substrate mimics. The mimics will be
synthesized by stereoselective organic synthesis techniques developed in the
PI's laboratory. The (Z) and (E)-alkene proline dipeptide mimics cannot be
isomerized, so they will be assayed as competitive inhibitors of Pin1. The
relative levels of Pin1 inhibition by cis and trans proline mimics of the Cdc25
substrate will help elucidate the mechanism by which Pin regulates mitosis. In
the second specific aim, the conformational selectivity of kinases upstream of
Pin1 that phosphorylate Cdc25 will be investigated. The role of Pin 1 in
mitosis will be investigated: 1) as an enzyme that isomerases phosphoSer-Pro
bonds in the substrate, Cdc25 phosphatase; 2) as a cofactor that binds to Cdc25
to regulate its activity in mitosis and 3) in Cdc25 protein folding and
chaperone studies. In the third specific aim, the mechanism of Pin1
peptidyl-proline isomerase activity will be investigated using isotope effects
and active site thiol titration. Using this information, a series of
mechanism-based inhibitors will be synthesized and assayed for Pin1 inhibition.
The mechanism-based inhibitors are considered rational design leads for
anti-cancer drugs. The successful completion of this proposal will lead to an
understanding of the mechanism of Pin1 PPIase activity to help elucidate its
essential role in signal transduction leading to mitosis.
描述:引脚1,一个新发现的有丝分裂信号调节器
转导是作用于磷酸丝氨酸-脯氨酸酰胺的酶。的
Pin 1独特的磷酸化依赖性肽基脯氨酰异构酶活性,
调节有丝分裂使其成为潜在癌症的非常有吸引力的新靶点
化疗药物Pin 1被假设为通过一个
构象开关,异构化一组蛋白质中的关键脯氨酸酰胺,
在有丝分裂过程中被上调。已知cdc 25特别与
Pin 1通过两个磷酸丝氨酸-脯氨酸基序。Cdc 25磷酸酶调节
有丝分裂特异性激酶Cdc 2与细胞周期蛋白B复合的活性。许多
脯氨酸需要在脯氨酸之前的酰胺键的异构化,
反式和顺式构象,以便折叠成生物活性的
构象肽基脯氨酰加速了折叠过程
异构酶(PPIase酶)。更好地机械地理解
Pin 1酶的PPIase活性将使人们了解PPIase依赖性
流程.第一个具体目标涉及构象对Pin 1的抑制
限制性顺式和反式脯氨酸底物模拟物。这些模仿者将
合成的立体选择性有机合成技术开发的
PI的实验室(Z)和(E)-烯烃脯氨酸二肽模拟物不能是
异构化,因此它们将被测定为Pin 1的竞争性抑制剂。的
Cdc 25的顺式和反式脯氨酸模拟物对Pin 1抑制的相对水平
底物将有助于阐明Pin调节有丝分裂的机制。在
第二个具体目标,激酶上游的构象选择性,
将研究磷酸化Cdc 25的Pin 1。Pin 1的作用
有丝分裂将被研究:1)作为一种酶,异构化磷酸丝氨酸-Pro
底物Cdc 25磷酸酶中的键; 2)作为与Cdc 25结合的辅因子
调节其在有丝分裂中的活性和3)Cdc 25蛋白折叠,
伴侣研究。在第三个具体目标中,Pin 1的机制
肽基脯氨酸异构酶活性将使用同位素效应进行研究
和活性位点硫醇滴定。利用这些信息,一系列
将合成基于机制的抑制剂并测定Pin 1抑制。
基于机理的抑制剂被认为是合理的设计,
抗癌药成功完成这一提案将导致
了解Pin 1 PPIase活性的机制,以帮助阐明其
在导致有丝分裂的信号转导中起重要作用。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('FELICIA A ETZKORN', 18)}}的其他基金
THE ROLE OF PIN1 IN MITOSIS WITH DESIGNED INHIBITORS
PIN1 在有丝分裂中与设计抑制剂的作用
- 批准号:
6335974 - 财政年份:2000
- 资助金额:
$ 17.87万 - 项目类别:
THE ROLE OF PIN1 IN MITOSIS WITH DESIGNED INHIBITORS
PIN1 在有丝分裂中与设计抑制剂的作用
- 批准号:
6526115 - 财政年份:2000
- 资助金额:
$ 17.87万 - 项目类别:
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