# Decoding the dynamic mechanism of allosteric activation in the cyclin-dependent kinase Cdk2

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2020 · $308,000

## Abstract

Project Abstract
 This project reaches towards a new paradigm for how conformational dynamics of protein kinases drive
their catalytic activation, and provides an important case study of how protein dynamics can be commandeered
to artificially control kinase activity with allosteric small molecules.
 The protein kinases are a large family of signaling proteins that control cell growth and proliferation in all
eukaryotic cells. Kinases behave like molecular switches, transitioning between catalytically active “on” and
inactive “off” states in a tightly controlled fashion to bring about prescribed changes in cell physiology. This
stringent regulatory control is widely disrupted in cancer, and targeting aberrant kinase activity with small-
molecule drugs is now an important component of many cancer treatments.
 Crystal structures have given us static pictures of the on and off states of kinases, but they tell us little
about how the proteins transition between these states, which is an inherently dynamic process. The nature of
these dynamic transitions and how they are perturbed in disease remain largely obscure, a fact that has
impeded our ability to design allosteric therapeutics that switch kinases to the off state by mimicking their
natural control mechanisms. Instead, existing kinase inhibitors work by binding to the highly conserved active
site, a mode of action that makes them poorly selective.
 The goal of this project is to use a combination of experimental methods that provide complementary
information about protein dynamics to determine how kinases transition between different conformational
states, and to understand how kinase dynamics can be commandeered by small-molecule drugs to artificially
modulate kinase function. Using nuclear magnetic resonance and optical spectroscopy applied to the cyclin-
dependent kinase Cdk2, a key regulator of cell cycle progression, we aim to reveal 1) the allosteric coupling
mechanism that links cyclin binding to activation of Cdk2, 2) how phosphorylation cooperates with the cyclin
subunit to tune protein dynamics and promote catalytic activity, and 3) how dynamic conformational changes in
Cdk2 control access of small-molecule ligands to allosteric pockets in the kinase. The insights from this work
will fundamentally advance our understanding of allosteric control mechanisms in proteins, and help set the
stage for the design of advanced allosteric therapeutics that effectively harness allostery to modulate kinase
function.

## Key facts

- **NIH application ID:** 9847972
- **Project number:** 5R01GM121515-03
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Nicholas Mark Levinson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $308,000
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9847972

## Citation

> US National Institutes of Health, RePORTER application 9847972, Decoding the dynamic mechanism of allosteric activation in the cyclin-dependent kinase Cdk2 (5R01GM121515-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9847972. Licensed CC0.

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