research papers
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 Mn2+ 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° 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.
Supporting information
Portable Document Format (PDF) file https://doi.org/10.1107/S0907444909047507/mv5032sup1.pdf |
PDB references: MST3 kinase domain, unliganded, crystal form I, 3a7f; form II, 3a7g; ADP complex, 3a7h; Mn-ADP complex, 3a7j; form III adenine complex, 3a7i