CAREER: The stereochemical basis of target selectivity encoded by specificity-determining loops in peptide-binding domains

职业:肽结合域中特异性决定环编码的靶标选择性的立体化学基础

基本信息

  • 批准号:
    2044958
  • 负责人:
  • 金额:
    $ 66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
    Continuing Grant
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-01 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Jeanine Amacher from Western Washington University to investigate how loops that are structurally conserved in various families of proteins affect their binding to other proteins and their functions as catalysts. Dr. Amacher’s group will determine how differences in the amino acid sequences that make up these loops help define the interactions that specifically targets a protein to its binding partner or affect its activity as an enzyme. Results from studies on these structural loops will reveal molecular principles to understand protein interactions that control how cells communicate. This project will train undergraduate and masters level graduate students in protein biochemistry and structural biology. The research and educational components of this project are integrated through specialized training in computational biology for undergraduate students and for their mentor. In addition, students at local primarily undergraduate institutions and community colleges will be connected with PhD students and postdoctoral research associates from regional research-intensive universities for “near-peer” mentoring through a regular Life Sciences Symposium hosted at Western Washington University. The importance of scientific communication in society will be integrated into an upper-level Honors “Bioethics of Emergent Technology in Biomedical Research” elective course to be offered at the host institution. This project will test the hypothesis that the selectivity and/or activity of catalytic and noncatalytic domains of critical signaling or regulatory proteins are determined by conserved structural loops. The studies will characterize structurally-conserved loops in bacterial sortases, two of which are known to affect specificity, along with site-specific contributions of previously identified specificity-determining loops in SH2 and SH3 domains of the human Src oncogene protein that mediate protein-protein interactions. Natural sequence variation will be applied to design chimeric proteins and other loop variants. The structure-function relationship of these loops with respect to encoding target specificity will be determined using FRET(Fluorescence Resonance Energy Transfer)-based activity assays, X-ray crystallography, and molecular dynamics simulations. In addition, biochemical and computational methods, including the structure prediction program ROSETTA, will be used to trace the evolutionary roots that lead to target specificity of conserved loop sequences. This project will identify common principles that broaden the understanding of the relationship between sequence and specificity in structurally-conserved loops across several protein families. Finally, a better understanding for the specificity of sortases will potentially expand the application of sortase-mediated ligation as a tool for protein engineering.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
有了这个奖项,化学部的生命过程化学计划正在资助西华盛顿大学的Jeanine Amacher博士,以研究在各种蛋白质家族中结构保守的环如何影响它们与其他蛋白质的结合及其作为催化剂的功能。Amacher博士的研究小组将确定组成这些环的氨基酸序列的差异如何帮助定义特异性靶向蛋白质与其结合伴侣或影响其作为酶的活性的相互作用。对这些结构环的研究结果将揭示分子原理,以了解控制细胞通信方式的蛋白质相互作用。该项目将培养蛋白质生物化学和结构生物学方面的本科生和硕士研究生。该项目的研究和教育组成部分通过对本科生及其导师的计算生物学专业培训进行整合。此外,当地主要是本科院校和社区学院的学生将通过在西华盛顿大学举办的定期生命科学研讨会,与来自区域研究密集型大学的博士生和博士后研究人员建立联系,进行“近同行”指导。科学交流在社会中的重要性将被纳入主办机构提供的高级荣誉“生物医学研究中新兴技术的生物伦理学”选修课程。本项目将检验关键信号或调节蛋白的催化和非催化结构域的选择性和/或活性是由保守的结构环决定的假设。这些研究将表征细菌分选酶中结构保守的环,其中两个已知影响特异性,沿着先前鉴定的特异性决定环在介导蛋白质-蛋白质相互作用的人Src癌基因蛋白的SH 2和SH 3结构域中的位点特异性贡献。天然序列变异将被应用于设计嵌合蛋白和其他环变体。将使用基于FRET(荧光共振能量转移)的活性测定、X射线晶体学和分子动力学模拟来确定这些环关于编码靶特异性的结构-功能关系。此外,生物化学和计算方法,包括结构预测程序ROSETTA,将用于追踪导致保守环序列的靶特异性的进化根源。这个项目将确定共同的原则,扩大了对序列和特异性之间的关系的理解,在结构上保守的环在几个蛋白质家族。最后,更好地了解分选酶的特异性将有可能扩大分选酶介导的连接作为蛋白质工程工具的应用。该奖项反映了NSF的法定使命,并通过使用基金会的知识价值和更广泛的影响进行评估,被认为值得支持。审查标准。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Comparative Analysis and Ancestral Sequence Reconstruction of Bacterial Sortase Family Proteins Generates Functional Ancestral Mutants with Different Sequence Specificities
  • DOI:
    10.3390/bacteria1020011
  • 发表时间:
    2022-06
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Jordan D. Valgardson;Sarah A. Struyvenberg;Zachary R. Sailer;I. Piper;Justin E. Svendsen;D. A. Johnson;Brandon A. Vogel;John M. Antos;M. Harms;J. Amacher
  • 通讯作者:
    Jordan D. Valgardson;Sarah A. Struyvenberg;Zachary R. Sailer;I. Piper;Justin E. Svendsen;D. A. Johnson;Brandon A. Vogel;John M. Antos;M. Harms;J. Amacher
Structural and biochemical analyses of selectivity determinants in chimeric Streptococcus Class A sortase enzymes
  • DOI:
    10.1002/pro.4266
  • 发表时间:
    2022-01-03
  • 期刊:
  • 影响因子:
    8
  • 作者:
    Gao, Melody;Johnson, D. Alex;Amacher, Jeanine F.
  • 通讯作者:
    Amacher, Jeanine F.
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Jeanine Amacher其他文献

Jeanine Amacher的其他文献

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{{ truncateString('Jeanine Amacher', 18)}}的其他基金

REU Site: Undergraduate Research in Chemistry at Western Washington University
REU 网站:西华盛顿大学化学本科生研究
  • 批准号:
    2243968
  • 财政年份:
    2023
  • 资助金额:
    $ 66万
  • 项目类别:
    Standard Grant
RUI: D3SC: The Role of Non-Motif Selectivity Determinants in Peptide-Binding Domain Interactions
RUI:D3SC:非基序选择性决定因素在肽结合域相互作用中的作用
  • 批准号:
    1904711
  • 财政年份:
    2019
  • 资助金额:
    $ 66万
  • 项目类别:
    Standard Grant

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点到轴手性转移:实现立体化学测定和对映选择性反应
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VCD激子手性法开发新型生物分子立体化学分析技术
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