Crystal structure of the catalytic domain of the mitotic checkpoint kinase Mps1 in complex with SP600125

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Matthew L H Chu1, Leonard M G Chavas, Kenneth T Douglas

  • 1School of Pharmacy and Pharmaceutical Sciences, Stopford Building, University of Manchester, Manchester, UK.

The Journal of Biological Chemistry
|May 16, 2008
PubMed

Insights

Researchers studied the protein kinase Monopolar Spindle 1 (Mps1), crucial for preventing aneuploidy. X-ray structures reveal how inhibitors bind, identifying a new pocket for designing targeted cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Chromosomal instability, linked to defective cell cycle checkpoints, drives malignant cell growth.
  • Monopolar spindle 1 (Mps1) is a protein kinase vital for preventing aneuploidy, making it a potential cancer therapeutic target.

Purpose of the Study:

  • To elucidate the molecular mechanisms of Mps1 inhibition by small molecules.
  • To provide structural insights for the rational design of specific Mps1 inhibitors.

Main Methods:

  • X-ray crystallography was used to determine the structure of Mps1.
  • Structures were obtained for Mps1 alone and in complex with the ATP-competitive inhibitor SP600125.

Main Results:

  • Mps1 exhibits a canonical protein kinase fold.
  • The inhibitor SP600125 binds within the ATP-binding site, stabilized by hydrophobic interactions.
  • A previously unexploited secondary pocket adjacent to the ATP-binding site was identified.

Conclusions:

  • The determined structures offer critical insights into Mps1-small molecule interactions.
  • The identified secondary pocket presents an opportunity for developing novel, specific Mps1 inhibitors.
  • These findings suggest potential avenues for Mps1 regulation in cancer therapy.

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