NMR DYNAMICS STUDY OF CHEMICAL ANALOGUES OF HIV-1 PROTEASE

HIV-1 蛋白酶化学类似物的核磁共振动力学研究

基本信息

  • 批准号:
    7954643
  • 负责人:
  • 金额:
    $ 0.47万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-03-01 至 2010-02-28
  • 项目状态:
    已结题

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Total chemical synthesis was used to prepare a series of unique chemical analogues of HIV-1 protease, where we systematically substituted the residues Gly51, Gly51' at the tips of the mobile 'flaps' (residues 37-61 in each domain of the protein homodimer) with L-Ala, D-Ala or Aib (alpha-aminoisobutyric acid) in both symmetric and asymmetric fashion. Such substitutions, although in regions distant from the catalytic aspartates, led in most cases to reduction of catalytic activity. In contrast to this, a 'covalent dimer' with L-Ala51 in one flap and D-Ala51' in another flap has shown native-like enzyme activity. We used continuous-wave and pulse EPR to characterize dynamic properties of flaps in spin-labeled analogues and found that the thermodynamic balance of the closed, semi-open and open ensembles (with respect to flaps) in HIV-1 protease analogues is perturbed in comparison to that of wild-type enzyme.We interpreted our results on the basis of Northrop's 'kinetic isomechanism' for aspartic proteases which employs a low-barrier hydrogen bond (LBHB) as the central part of the concept. We have developed Northrop's concept further to take into account dynamic properties of the protein and the non-equivalence of the flaps in the ligand-bound enzyme. We proposed a mechanical coupling of motions of the flaps and the catalytic residues Asp25 and Asp25'. On a mechanistic level, opening of the flaps corresponds to shortening of the distance between catalytic residues Asp25 and Asp25' thus promoting formation of the LBHB, and vice versa.Our goal is to employ NMR methods to detect and unambiguously prove presence of LBHB. In addition we would like to determine ionization states of catalytic residues for chemical analogues which demonstrate distinctly different protein dynamics and thus attempt to correlate dynamic properties of the enzyme with its chemical mechanism.
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项目成果

期刊论文数量(0)
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会议论文数量(0)
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STEPHEN B.H. KENT其他文献

STEPHEN B.H. KENT的其他文献

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{{ truncateString('STEPHEN B.H. KENT', 18)}}的其他基金

Novel Approaches to the Total Chemical Synthesis of Lasso Peptides as a Scaffold
套索肽作为支架的全化学合成新方法
  • 批准号:
    8868928
  • 财政年份:
    2014
  • 资助金额:
    $ 0.47万
  • 项目类别:
Design, Total Synthesis & Properties of Novel Chemical Analogs of Human Insulin
设计、全合成
  • 批准号:
    8269657
  • 财政年份:
    2010
  • 资助金额:
    $ 0.47万
  • 项目类别:
Core D2: Chemical Synthesis
核心 D2:化学合成
  • 批准号:
    7922835
  • 财政年份:
    2010
  • 资助金额:
    $ 0.47万
  • 项目类别:
Design, Total Synthesis & Properties of Novel Chemical Analogs of Human Insulin
设计、全合成
  • 批准号:
    8473857
  • 财政年份:
    2010
  • 资助金额:
    $ 0.47万
  • 项目类别:
Design, Total Synthesis & Properties of Novel Chemical Analogs of Human Insulin
设计、全合成
  • 批准号:
    8009137
  • 财政年份:
    2010
  • 资助金额:
    $ 0.47万
  • 项目类别:
Design, Total Synthesis & Properties of Novel Chemical Analogs of Human Insulin
设计、全合成
  • 批准号:
    8113870
  • 财政年份:
    2010
  • 资助金额:
    $ 0.47万
  • 项目类别:
TRAINING IN THE USE OF BRUKER AND VARIAN SPECTROMETERS AND NMR
布鲁克和瓦里安光谱仪和核磁共振的使用培训
  • 批准号:
    7954645
  • 财政年份:
    2009
  • 资助金额:
    $ 0.47万
  • 项目类别:
PROTONATION STATES OF CATALYTIC ASP25 AND ASP25' IN 13C LABELED HIV-1 PROTEASE
13C 标记的 HIV-1 蛋白酶中催化 ASP25 和 ASP25 的质子化态
  • 批准号:
    7954644
  • 财政年份:
    2009
  • 资助金额:
    $ 0.47万
  • 项目类别:
Systematic Approach to the Chemical Synthesis (RMI)
化学合成的系统方法 (RMI)
  • 批准号:
    7014822
  • 财政年份:
    2005
  • 资助金额:
    $ 0.47万
  • 项目类别:
A Systematic Approach to the Chemical Synthesis (RMI)
化学合成 (RMI) 的系统方法
  • 批准号:
    7265325
  • 财政年份:
    2005
  • 资助金额:
    $ 0.47万
  • 项目类别:
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