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Identification of a novel target site for ATP-independent ERK2 inhibitors

Mayu Yoshida1, Haruna Nagao2, Hajime Sugiyama3

  • 1Graduate School of Science, Osaka Prefecture University, Osaka, 599-8531, Japan.

Biochemical and Biophysical Research Communications
|January 22, 2022
PubMed

Insights

Extracellular signal-regulated kinase 2 (ERK2) is a cancer drug target. Researchers discovered a novel binding site for an ERK2 inhibitor, compound 1, challenging previous assumptions and opening new therapeutic avenues.

Area of Science:

  • Molecular biology
  • Drug discovery
  • Structural biology

Background:

  • Extracellular signal-regulated kinase 2 (ERK2) is crucial for cell proliferation and differentiation.
  • ERK2 is a significant drug target for various diseases, including cancers.
  • Targeting an allosteric site for ERK2 inhibition was previously explored.

Purpose of the Study:

  • To investigate the binding mechanism of a potential ERK2 inhibitor, compound 1.
  • To determine the actual binding site of compound 1 on ERK2.
  • To explore novel strategies for developing ERK2-targeted therapies.

Main Methods:

  • In silico screening was employed to identify potential ERK2 inhibitors.
  • Competitive binding assays were performed to validate the binding site.
  • X-ray crystallography was used to determine the high-resolution structure of ERK2 complexed with compound 1.

Main Results:

  • In silico screening suggested compound 1 binds to an allosteric site of ERK2.
  • Competitive binding assays revealed compound 1 does not bind to the predicted allosteric site.
  • Crystal structure analysis identified a novel binding site for compound 1 on ERK2.

Conclusions:

  • The actual binding site of compound 1 on ERK2 is different from the initially predicted allosteric site.
  • This discovery validates the potential for developing novel classes of ERK2 inhibitors.
  • The findings open new avenues for targeting ERK2 in cancer and other diseases.
Keywords:
ATP-independent inhibitorActivation loopCancerERK2Molecular dynamics simulationX-ray crystal structure

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