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Studying how a general allosteric site regulates protein kinase function

研究一般变构位点如何调节蛋白激酶功能

基本信息

批准号：
8595027
负责人：
Terry Justin Rettenmaier
金额：
$ 3.56万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8595027
关键词：
Adverse effects Allosteric Site Binding Biochemical Biological Assay Cell Culture Techniques Cell membrane Cells Clinic Clinical Defect Development Dimethyl Sulfoxide Event Exhibits Genetic Techniques Goals Grant Health Human In Vitro Individual Knowledge Lead Ligands Malignant Neoplasms Mass Spectrum Analysis Medicine Melanoma Cell Methods Molecular Movement Neoplasm Metastasis PDPK1 gene Peptides Pharmaceutical Preparations Phosphorylation Phosphotransferases Protein Kinase Protein Kinase Inhibitors Proteins Proteomics ROCK1 gene Relative (related person)Research Role Science Series Signal Pathway Signal Transduction Structure Substrate Specificity Testing Therapeutic Work analog base cancer cell cancer therapy cell motility chemical genetics chemical synthesis drug discovery in vitro activity kinase inhibitor mutant novel therapeutics prevent protein kinase inhibitor public health relevance research study scaffold small molecule standard of care thiophosphate tool

项目摘要

DESCRIPTION (provided by applicant): Small-molecule inhibitors of protein kinases have revolutionized biomedical science. In the clinic, protein kinase inhibitors have ushered in the era of personalized medicine by transforming the standard of care for a variety of cancers. At the bench, the widespread use of protein kinase inhibitors as research tools has significantly advanced our knowledge of the roles of protein kinases in signaling pathways. However, the molecular mechanisms that regulate the function of individual kinases remain poorly understood. Given the proven clinical value of kinase-directed therapeutics, a detailed understanding of kinase regulatory mechanisms can significantly impact human health by identifying new ways to modulate kinase function. The long-term goal of this proposal is to determine how a general allosteric site regulates the substrate specificity and subcellular localization of the protein kinases. This proposal focuses on the protein kinase PDK1 where this allosteric site, known as the PIF pocket, is required for the phosphorylation of most PDK1 substrates. The PIF pocket may also promote cancer cell motility. Our lab recently identified small molecules that bind to the PIF pocket in cells. We hypothesize that these PIF-pocket ligands will disrupt the interaction between PDK1 and a subset of its substrates and effector proteins, thereby granting a rapid and reversible way to perturb PIF pocket function. The work proposed here aims to use our PIF-pocket ligands 1) to study how the PIF pocket determines the substrate specificity of PDK1 and 2) to study how the PIF pocket promotes cancer cell motility. To accomplish the first aim, we will identify PDK1 substrates by mass spectrometry and determine the sensitivity of their phosphorylation to our PIF-pocket ligands. To accomplish the second aim, we will characterize the role of the PIF pocket in the motility of highly aggressive melanoma cells grown in 3D culture. These studies will highlight the importance of this general allosteric site in regulating protein kinase function. This concept may alter the landscape of kinase drug discovery and lead to the development of a new class of kinase-directed therapies.

描述（由申请人提供）：蛋白激酶的小分子抑制剂彻底改变了生物医学科学。在临床上，蛋白激酶抑制剂已经迎来了时代