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Structures of human MST3 kinase in complex with adenine, ADP and Mn2+

Tzu-Ping Ko1, Wen-Yih Jeng, Chia-I Liu

  • 1Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.

Acta Crystallographica. Section D, Biological Crystallography
|February 4, 2010
PubMed

Insights

Mammalian sterile 20-related kinase 3 (MST3) structures reveal its catalytic domain, preferred manganese cofactor, and activation mechanism. These findings aid in designing potent MST3 inhibitors for cell growth and apoptosis regulation.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Molecular Biology

Background:

  • The MST (mammalian sterile 20-related kinase) family are serine/threonine kinases involved in cell growth and transformation.
  • MST3 protein has a catalytic domain and a regulatory domain, crucial for apoptosis.
  • Caspase cleavage and autophosphorylation activate MST3.

Purpose of the Study:

  • To present crystal structures of the MST3 catalytic domain.
  • To elucidate the enzyme's interaction with its preferred cofactor, manganese, and ADP.
  • To understand the structural basis of MST3 activation.

Main Methods:

  • X-ray crystallography was used to determine five crystal structures of the MST3 catalytic domain.
  • Structures include complexes with ADP and manganese, and with adenine.
  • Comparative structural analysis with related kinases was performed.

Main Results:

  • The MST3 catalytic domain adopts a two-lobe structure typical of protein kinases.
  • Specific interactions of ADP and Mn(2+) within the nucleotide-binding site were detailed.
  • Phosphorylation of Thr178 in the activation loop, stabilized by Arg143 and Arg176, was observed, indicating an active conformation.

Conclusions:

  • The determined structures provide detailed insights into MST3's catalytic mechanism and cofactor preference.
  • The unique orientation of the activation loop suggests a conserved activation mechanism across kinases.
  • These findings offer a structural basis for the rational design of MST3 inhibitors.

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