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Publication Abstract from PubMed

The MST family is a subclass of mammalian serine/threonine kinases that are related to the yeast sterile-20 protein and are implicated in regulating cell growth and transformation. The MST3 protein contains a 300-residue catalytic domain and a 130-residue regulatory domain, which can be cleaved by caspase and activated by autophosphorylation, promoting apoptosis. Here, five crystal structures of the catalytic domain of MST3 are presented, including a complex with ADP and manganese, a unique cofactor preferred by the enzyme, and a complex with adenine. Similar to other protein kinases, the catalytic domain of MST3 folds into two lobes: the smaller N lobe forms the nucleotide-binding site and the larger C lobe recognizes the polypeptide substrate. The bound ADP and Mn(2+) ions are covered by a glycine-rich loop and held in place by Asn149 and Asp162. A different orientation was observed for the ligand in the MST3-adenine complex. In the activation loop, the side chain of Thr178 is phosphorylated and is sandwiched by Arg143 and Arg176. Comparison of this structure with other similar kinase structures shows a 180 degrees rotation of the loop, leading to activation of the enzyme. The well defined protein-ligand interactions also provide useful information for the design of potent inhibitors.

Structures of human MST3 kinase in complex with adenine, ADP and Mn2+.,Ko TP, Jeng WY, Liu CI, Lai MD, Wu CL, Chang WJ, Shr HL, Lu TJ, Wang AH Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):145-54. Epub 2010 Jan 22. PMID:20124694^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.