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Dynamics of Ligand Binding and Protein Kinase Regulation

配体结合动力学和蛋白激酶调节

基本信息

批准号：
10625416
负责人：
Markus A Seeliger
金额：
$ 40.77万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625416
关键词：
Affect Affinity Binding Biological Assay Biological Process Biology Catalytic Domain Cells Chemicals Clinical Collaborations Computer Models Computing Methodologies Conserved Sequence Cyclic AMP-Dependent Protein Kinases Data Data Set Development Disease Dissociation Drug Modelings Drug resistance Enzymes Family Foundations Goals Health Human In Vitro Kinetics Knowledge Ligand Binding Malignant Neoplasms Medicine Molecular Molecular Conformation Mutation Pharmaceutical Preparations Phenotype Phosphotransferases Process Productivity Protein Engineering Protein Kinase Protein Tyrosine Kinase Proteins Public Health Regulation Research Roentgen Rays Role Signal Pathway Signal Transduction Specificity Testing design inhibitor kinase inhibitor pharmacokinetics and pharmacodynamics pressure protein structure resistance mechanism resistance mutation src-Family Kinases therapeutic target

项目摘要

PROJECT SUMMARY. Protein kinases are a large family of ubiquitous signaling enzymes in human cells. Their dysregulation often underlies diseases such as cancer, making them excellent therapeutic targets. However, the high structural and sequence conservation of the protein kinase catalytic domains has complicated the development of specific inhibitors. Many clinically-successful kinase inhibitors achieve specificity in part by binding only to distinct kinase conformations. While the analysis of thousands of X-ray crystal structures of protein kinases has shown that a single kinase domain can access different active and inactive conformations, little is known about how kinases interconvert between the conformations. The rationale of this proposal is that a quantitative understanding of the stability of these conformations and the dynamics of their interconversion are key to understanding kinase activity, regulation, ligand binding and drug resistance in health and disease states. The objective of this project is to obtain a comprehensive understanding of the role of conformational dynamics in kinase function, regulation and drug resistance through altered drug dissociation rates. This proposal is part of a continuum of research centered around three questions: Q1: How do regulatory domains, interacting proteins and disease-relevant mutations affect the conformational dynamics of tyrosine kinases? Our goal is to determine how the solution dynamics of Src kinase domain responds to these biologically important perturbations. Q2: What are the molecular and cellular determinants of ligand-binding kinetics? We will test our computational model for the drug binding process experimentally, both in vitro and in cells, by assessing drug affinities and binding and dissociation kinetics. Our goal is to determine quantitative parameters for the drug binding process and how the alteration of these parameters by mutation underlies drug resistance. Q3: How can phenotypic clustering of inhibition data be used to reveal hidden kinase features? Our goal is to mine kinome-wide inhibition datasets to group kinases by their inhibition phenotype, which reflects on the evolutionary pressure and adaption that other biological functions impose on kinases. We will use structural approaches (X-ray and NMR), cellular drug binding and activity assays, ligand binding kinetics, protein engineering, chemical biology and diverse computational methods. A network of productive collaborations supports this project. The impact of this project is to provide clinicians with the mechanism of resistance mutations, medicinal chemists with kinase inhibitor pharmacodynamics and pharmacokinetics and cell biologists with parameters to understand kinase signaling. The long-term goal is to lay the foundation for the design of safe, effective, and sufficiently specific inhibitors of disease-associated protein kinases.

项目总结。蛋白激酶是人类细胞中普遍存在的一大类信号酶。他们的

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Biochemical Studies of Systemic Lupus Erythematosus-Associated Mutations in Nonreceptor Tyrosine Kinases Ack1 and Brk.

非受体酪氨酸激酶ACK1和BRK中与全身性红斑狼疮相关突变的生化研究。

DOI：
10.1021/acs.biochem.2c00685
发表时间：
2023-03-21
期刊：
BIOCHEMISTRY
影响因子：
2.9
作者：
Kan, Yagmur;Paung, YiTing;Kim, Yunyoung;Seeliger, Markus A.;Miller, W. Todd
通讯作者：
Miller, W. Todd

A Novel In Vitro CypD-Mediated p53 Aggregation Assay Suggests a Model for Mitochondrial Permeability Transition by Chaperone Systems.

DOI：
10.1016/j.jmb.2016.08.001
发表时间：
2016-10-09
期刊：
Journal of molecular biology
影响因子：
5.6
作者：
Lebedev I;Nemajerova A;Foda ZH;Kornaj M;Tong M;Moll UM;Seeliger MA
通讯作者：
Seeliger MA

Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites.

DOI：
10.1038/s41467-017-02240-6
发表时间：
2017-12-18
期刊：
Nature communications
影响因子：
16.6
作者：
Tong M;Pelton JG;Gill ML;Zhang W;Picart F;Seeliger MA
通讯作者：
Seeliger MA

Targeting the Hemopexin-like Domain of Latent Matrix Metalloproteinase-9 (proMMP-9) with a Small Molecule Inhibitor Prevents the Formation of Focal Adhesion Junctions.

DOI：
10.1021/acschembio.7b00758
发表时间：
2017-11-17
期刊：
ACS chemical biology
影响因子：
4
作者：
Alford VM;Kamath A;Ren X;Kumar K;Gan Q;Awwa M;Tong M;Seeliger MA;Cao J;Ojima I;Sampson NS
通讯作者：
Sampson NS

More Diversity Yields a Clearer Picture into the Architecture of the Protein Kinase Domain.

更多的多样性让我们对蛋白激酶结构域的结构有了更清晰的了解。