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

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.
Pin 1,一个新发现的有丝分裂信号调节因子

项目成果

期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Solvent-dependent stereoselectivity in a Still-Wittig rearrangement: an experimental and ab initio study.
Still-Wittig 重排中溶剂依赖性立体选择性:实验和从头开始研究。
  • DOI:
    10.1021/ol015764d
  • 发表时间:
    2001
  • 期刊:
  • 影响因子:
    5.2
  • 作者:
    Hart,SA;Trindle,CO;Etzkorn,FA
  • 通讯作者:
    Etzkorn,FA
Loop dependence of the stability and dynamics of nucleic acid hairpins.
  • DOI:
    10.1093/nar/gkm1083
  • 发表时间:
    2008-03
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Kuznetsov SV;Ren CC;Woodson SA;Ansari A
  • 通讯作者:
    Ansari A
Conformationally locked isostere of phosphoSer-cis-Pro inhibits Pin1 23-fold better than phosphoSer-trans-Pro isostere.
  • DOI:
    10.1021/ja046396m
  • 发表时间:
    2004-11
  • 期刊:
  • 影响因子:
    15
  • 作者:
    Xiaodong J. Wang;Bailing Xu;Ashley B Mullins;Freda K Neiler;F. Etzkorn
  • 通讯作者:
    Xiaodong J. Wang;Bailing Xu;Ashley B Mullins;Freda K Neiler;F. Etzkorn
Hydroxyl radical footprinting in vivo: mapping macromolecular structures with synchrotron radiation.
体内羟基自由基足迹:用同步辐射绘制大分子结构。
  • DOI:
    10.1093/nar/gkl291
  • 发表时间:
    2006-05-08
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Adilakshmi, Tadepalli;Lease, Richard A.;Woodson, Sarah A.
  • 通讯作者:
    Woodson, Sarah A.
Structural requirement for Mg2+ binding in the group I intron core.
I 组内含子核心中 Mg2 结合的结构要求。
  • DOI:
    10.1016/s0022-2836(03)00430-3
  • 发表时间:
    2003
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Rangan,Prashanth;Woodson,SarahA
  • 通讯作者:
    Woodson,SarahA
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FELICIA A ETZKORN其他文献

FELICIA A ETZKORN的其他文献

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{{ truncateString('FELICIA A ETZKORN', 18)}}的其他基金

Liquid Chromatograph-Tandem Mass Spectrometer
液相色谱-串联质谱仪
  • 批准号:
    6441317
  • 财政年份:
    2002
  • 资助金额:
    $ 17.89万
  • 项目类别:
Designed Inhibitors of Pin1 in Mitosis
有丝分裂中 Pin1 的设计抑制剂
  • 批准号:
    7270460
  • 财政年份:
    2000
  • 资助金额:
    $ 17.89万
  • 项目类别:
Designed Inhibitors of Pin1 in Mitosis
有丝分裂中 Pin1 的设计抑制剂
  • 批准号:
    7031406
  • 财政年份:
    2000
  • 资助金额:
    $ 17.89万
  • 项目类别:
Designed Inhibitors of Pin1 in Mitosis
有丝分裂中 Pin1 的设计抑制剂
  • 批准号:
    7477724
  • 财政年份:
    2000
  • 资助金额:
    $ 17.89万
  • 项目类别:
Designed Inhibitors of Pin1 in Mitosis
有丝分裂中 Pin1 的设计抑制剂
  • 批准号:
    7667517
  • 财政年份:
    2000
  • 资助金额:
    $ 17.89万
  • 项目类别:
Designed Inhibitors of Pin1 in Mitosis
有丝分裂中 Pin1 的设计抑制剂
  • 批准号:
    7126863
  • 财政年份:
    2000
  • 资助金额:
    $ 17.89万
  • 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:
    6335974
  • 财政年份:
    2000
  • 资助金额:
    $ 17.89万
  • 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:
    6387319
  • 财政年份:
    2000
  • 资助金额:
    $ 17.89万
  • 项目类别:
MIMICS OF HELIX TURN HELIX PEPTIDES
螺旋转角螺旋肽的模拟物
  • 批准号:
    6436988
  • 财政年份:
    1997
  • 资助金额:
    $ 17.89万
  • 项目类别:
MIMICS OF HELIX TURN HELIX PEPTIDES
螺旋转角螺旋肽的模拟物
  • 批准号:
    6180628
  • 财政年份:
    1997
  • 资助金额:
    $ 17.89万
  • 项目类别:

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细胞周期蛋白对中性粒细胞功能的调节
  • 批准号:
    MR/R02149X/1
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Musashi 在细胞周期蛋白调节中的作用
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细胞周期蛋白在细胞凋亡中的作用
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    7226655
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HIV-1 和细胞周期蛋白之间的相互作用
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  • 财政年份:
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  • 资助金额:
    $ 17.89万
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