title: Structures of human MST3 kinase in complex with adenine, ADP and Mn2+.
abstract: 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.
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.forename: Wen-Yih
authors.initials: WY
authors.lastname: Jeng
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Liu
authors.forename: Ming-Derg
authors.initials: MD
authors.lastname: Lai
authors.forename: Chun-Lan
authors.initials: CL
authors.lastname: Wu
authors.forename: Wei-Jung
authors.initials: WJ
authors.lastname: Chang
authors.forename: Hui-Lin
authors.initials: HL
authors.lastname: Shr
authors.forename: Te-Jung
authors.initials: TJ
authors.lastname: Lu
authors.forename: Andrew H-J
authors.initials: AH
authors.lastname: Wang
mesh_terms: D000225:Adenine / Q000737:chemistry* / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000595:Amino Acid Sequence; D020134:Catalytic Domain; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008345:Manganese / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D000099317:Hippo Kinases
chemical_list: D000225:Adenine; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D008345:Manganese; D017346:Protein Serine-Threonine Kinases; C109163:STK24 protein, human; D000099317:Hippo Kinases