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Chemical probes of protein histidine phosphatase activity

蛋白质组氨酸磷酸酶活性的化学探针

基本信息

批准号：
9899261
负责人：
AMY M BARRIOS
金额：
$ 22.88万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9899261
关键词：
Accounting Amino Acids Antibodies Autoimmunity Biological Biological Assay Biology Cardiovascular Diseases Cells Chemicals Chromatin Clinic Copper Dependence Detection Development Disease Dose Enzymes Family Fluorogenic Substrate Future GTP-Binding Proteins Goals High Pressure Liquid Chromatography Histidine Human In Vitro Individual Ions Kinetics Laboratories Lead Libraries Malignant Neoplasms Mammalian Cell Mammals Mediating Metabolism Methods Monitor Peptides Phosphoric Monoester Hydrolases Phosphorylation Phosphotyrosine Play Potassium Channel Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Proteomics Regulation Reporting Research Role Series Serine Signal Pathway Signaling Protein Site Technology Threonine Tyrosine Kinase Inhibitor Tyrosine Phosphorylation Validation Work assay development counterscreen design experience high throughput screening in vitro activity in vivo inhibitor/antagonist innovation innovative technologies mimetics nanomolar nitrophenylphosphate novel phosphatase inhibitor phosphohistidine programs protein protein interaction protein-histidine kinase response screening technology research and development tool

项目摘要

Project Summary Protein histidine phosphorylation plays an important role in several key signaling pathways in mammals but is very poorly understood. The main reasons for this dearth of information about histidine phosphorylation are the relative instability of pHis as compared to pSer, pThr, and pTyr and a complete lack of chemical tools available to monitor and modulate the enzymes involved in histidine phosphorylation and dephosphorylation. In this project, we will develop fluorogenic assays that can be applied to monitoring both histidine phosphatase and histidine kinase activity and identify the first histidine phosphatase inhibitors from a series of focused screening efforts. This project is submitted in response to PAR-17-046 “Exploratory Research for Technology Development (R21)” and, as indicated in the PAR, is focused on the development of innovative, enabling technologies for studying histidine phosphorylation and dephosphorylation. Future work would center around applying these tools to developing a better understanding of the roles individual histidine phosphatases in mammalian cells.

项目摘要蛋白质组氨酸磷酸化在几个关键信号通路中起着重要作用，哺乳动物，但了解甚少。缺乏关于以下方面信息的主要原因是：组氨酸磷酸化是pHis与pSer、pThr和pTyr相比的相对不稳定性完全缺乏化学工具来监测和调节相关的酶组氨酸磷酸化和去磷酸化。在这个项目中，我们将开发荧光可用于监测组氨酸磷酸酶和组氨酸激酶活性的测定并从一系列集中的筛选工作中鉴定出第一批组氨酸磷酸酶抑制剂。本项目是根据PAR-17-046“技术探索性研究”提交的发展（R21）”，并如PAR所示，重点是发展创新，使研究组氨酸磷酸化和去磷酸化的技术成为可能。未来工作将围绕应用这些工具，以更好地理解这些角色，哺乳动物细胞中的单个组氨酸磷酸酶。