Structure of the Brachydanio rerio Polo-like kinase 1 (Plk1) catalytic domain in complex with an extended inhibitor targeting the adaptive pocket of the enzyme
Structure of the Brachydanio rerio Polo-like kinase 1 (Plk1) catalytic domain in complex with an extended inhibitor targeting the adaptive pocket of the enzyme
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DOI：
10.1107/s1744309108019623
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发表时间：
2008-08-01
影响因子：
0.9
通讯作者：
Romanowski, Michael J.
中科院分区：
文献类型：
--
作者：
Elling, Robert A.;Fucini, Raymond V.;Romanowski, Michael J.
Polo-like kinase1(Plk1)是Polo-like丝氨酸/苏氨酸激酶家族的一员，参与调节细胞周期进程和胞质分裂，是抗癌药物开发的一个有吸引力的靶点。该酶的催化结构域与另一种有丝分裂酶Aurora A具有显著的氨基酸同源性和结构相似性。在筛选Aurora A的ATP竞争性化合物文库时，发现了一种对小鼠Aurora A低亲和力但对人和斑马鱼Plk1(分别为hPlk1和zPlk1)具有亚微摩尔效力的含尿素的抑制物。斑马鱼Plk1激酶域-抑制物复合体的晶体结构表明，小分子占据了嘌呤口袋，并越过催化赖氨酸进入活性部位的适应性区域。分析这种蛋白质-抑制物复合体以及与其他激酶共结晶的类似小分子的结构有助于理解Plk1抑制物的特异性，并首次证明Plk1可以容纳扩展的ATP竞争化合物，这些化合物向适应性口袋投射，并帮助酶对其激活片段进行排序。
Polo-like kinase 1 (Plk1) is a member of the Polo-like kinase family of serine/threonine kinases involved in the regulation of cell-cycle progression and cytokinesis and is an attractive target for the development of anticancer therapeutics. The catalytic domain of this enzyme shares significant primary amino-acid homology and structural similarity with another mitotic kinase, Aurora A. While screening an Aurora A library of ATP-competitive compounds, a urea-containing inhibitor with low affinity for mouse Aurora A but with submicromolar potency for human and zebrafish Plk1 (hPlk1 and zPlk1, respectively) was identified. A crystal structure of the zebrafish Plk1 kinase domain-inhibitor complex reveals that the small molecule occupies the purine pocket and extends past the catalytic lysine into the adaptive region of the active site. Analysis of the structures of this protein-inhibitor complex and of similar small molecules cocrystallized with other kinases facilitates understanding of the specificity of the inhibitor for Plk1 and documents for the first time that Plk1 can accommodate extended ATP-competitive compounds that project toward the adaptive pocket and help the enzyme order its activation segment.