The structural mechanisms that underpin mitotic kinase activation

被引:14
作者
Dodson, Charlotte A.
Haq, Tamanna [1 ]
Yeoh, Sharon [2 ]
Fry, Andrew M. [1 ]
Bayliss, Richard [1 ]
机构
[1] Univ Leicester, Henry Wellcome Labs Struct Biol, Dept Biochem, Leicester LE1 9HN, Leics, England
[2] Univ Leicester, Henry Wellcome Labs Struct Biol, Ctr Translat Therapeut, Leicester LE1 9HN, Leics, England
基金
英国惠康基金;
关键词
activation mechanism; Aurora-A; drug discovery; Nek7; protein kinase; structural biology; PROTEIN-KINASES; AURORA-A; SPINDLE FORMATION; RESISTANT AURORA; NEK7; KINASE; PHOSPHORYLATION; MUTANTS; BINDING; MLN8054; FAMILY;
D O I
10.1042/BST20130066
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In eukaryotic cells, the peak of protein phosphorylation occurs during mitosis, switching the activities of a significant proportion of proteins and orchestrating a wholesale reorganization of cell shape and internal architecture. Most mitotic protein phosphorylation events are catalysed by a small subset of serine/threonine protein kinases. These include members of the Cdk (cyclin-dependent kinase), Plk (Polo-like kinase), Aurora, Nek (NimA-related kinase) and Bub families, as well as Haspin, Greatwall and Mps1/TTK. There has been steady progress in resolving the structural mechanisms that regulate the catalytic activities of these mitotic kinases. From structural and biochemical perspectives, kinase activation appears not as a binary process (from inactive to active), but as a series of states that exhibit varying degrees of activity. In its lowest activity state, a mitotic kinase may exhibit diverse autoinhibited or inactive conformations. Kinase activation proceeds via phosphorylation and/or association with a binding partner. These remodel the structure into an active conformation that is common to almost all protein kinases. However, all mitotic kinases of known structure have divergent features, many of which are key to understanding their specific regulatory mechanisms. Finally, mitotic kinases are an important class of drug target, and their structural characterization has facilitated the rational design of chemical inhibitors.
引用
收藏
页码:1037 / 1041
页数:5
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