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Structure of extracellular signal-regulated kinase 2 in complex with ATP and ADP

Jun Zhang1, Paul Shapiro, Edwin Pozharski

  • 1Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 Penn Street, Baltimore, MD 21201, USA.

Acta Crystallographica. Section F, Structural Biology and Crystallization Communications
|November 30, 2012
PubMed

Insights

Extracellular signal-regulated kinases (ERK1 and ERK2) are key in cancer. Understanding their ATP-binding pocket structures, determined in this study, aids in designing new anticancer drugs to inhibit ERK activity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2) are mitogen-activated protein (MAP) kinases.
  • Constitutive activation of ERK proteins is implicated in human tumor development and progression.
  • ERK1 and ERK2 represent promising therapeutic targets for anticancer drug development.

Purpose of the Study:

  • To determine the detailed structures of ERK2 in its apo form and complexed with ATP and ADP.
  • To provide structural insights for designing novel ligands that inhibit ERK activity by targeting the ATP-binding pocket.

Main Methods:

  • X-ray crystallography was used to determine the structures of apo-form ERK2 and its complexes with ATP and ADP.
  • Structural comparison with the homolog cyclin-dependent kinase 2 was performed.

Main Results:

  • The structures of apo-ERK2, ERK2-ATP complex, and ERK2-ADP complex were elucidated.
  • Differences in magnesium-mediated ATP binding were observed compared to cyclin-dependent kinase 2.
  • Minor conformational changes upon substrate binding were localized to active-site residues.

Conclusions:

  • Structural data of ERK2-ligand complexes offer valuable information for rational drug design.
  • Targeting the ATP-binding pocket of ERK1 and ERK2 is a viable strategy for developing anticancer therapeutics.

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