# Dynamics of inhibitor binding and regulation of protein tyrosine kinases

> **NIH NIH R35** · STATE UNIVERSITY NEW YORK STONY BROOK · 2020 · $397,504

## Abstract

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, when drug
specificity can be achieved. However, the high structural and sequence conservation of the protein kinase
catalytic domains has complicated the development of specific inhibitors. The few 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 and
ligand binding in health and disease states.
The objective of this project is to describe the kinetic and equilibrium parameters for the conformational
interconversions within the kinase domains of tyrosine kinases Src, Abl, Brk and the promiscuous drug-binding
tyrosine kinase DDR1. This proposal is part of a continuum of research centered around four questions that
concern the role of conformational dynamics of protein kinases in kinase regulation (Q1), allosteric modulation
(Q2), ligand binding kinetics (Q3) and drug specificity/kinase promiscuity (Q4):
Q1: What are the thermodynamics and kinetics of conformational exchange in tyrosine kinases?
Q2: How are allosteric signals communicated through protein domains and how can binding sites for allosteric
 regulators be predicted?
Q3: What are the molecular determinants of ligand-binding kinetics?
Q4: Why do some kinases bind inhibitors promiscuously and how can specific inhibitors with cellular potency be
developed?
The PI and his team will study these questions through a combination of structural methods (X-ray and NMR),
ligand binding kinetics, protein engineering, chemical biology and 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, cell biologists with parameters to understand kinase signaling and medicinal
chemists with parameters to modulate ligand binding kinetics. The long-term goal is to lay the foundation for the
design of safe and effective, sufficiently specific, inhibitors of disease-associated protein kinases.

## Key facts

- **NIH application ID:** 9925795
- **Project number:** 5R35GM119437-05
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Markus A Seeliger
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,504
- **Award type:** 5
- **Project period:** 2016-07-15 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9925795

## Citation

> US National Institutes of Health, RePORTER application 9925795, Dynamics of inhibitor binding and regulation of protein tyrosine kinases (5R35GM119437-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9925795. Licensed CC0.

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