Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1
Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1
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DOI：
10.1074/jbc.m406703200
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发表时间：
2004-10-15
影响因子：
4.8
通讯作者：
Stout, TJ
中科院分区：
文献类型：
--
作者：
Lougheed, JC;Chen, RH;Stout, TJ
ACK 1是一种多结构域非受体酪氨酸激酶，是Cdc 42 GT3的效应子。ACK家族的成员具有独特的结构域排序，并且是已知与Cdc 42相互作用的唯一酪氨酸激酶。与许多蛋白激酶相反，ACK 1在磷酸化后活性仅适度增加。我们已经解决了在非磷酸化和磷酸化状态下的人ACK 1激酶结构域的晶体结构。这些结构的比较表明，ACK 1采用独立于磷酸化的活化构象。此外，未磷酸化的活化环是结构化的，其构象类似于活化的酪氨酸激酶中所见。除载脂蛋白结构外，复合物还与不可水解的核苷酸类似物（腺苷5 '-（β，γ-亚甲基三磷酸））和天然产物脱溴海美纳醛二辛（许多蛋白激酶的一般抑制剂）一起存在。这些结构的分析揭示了一个典型的激酶折叠，预组织成活化构象，和一个不寻常的底物结合裂缝。
ACK1 is a multidomain non-receptor tyrosine kinase that is an effector of the Cdc42 GTPase. Members of the ACK family have a unique domain ordering and are the only tyrosine kinases known to interact with Cdc42. In contrast with many protein kinases, ACK1 has only a modest increase in activity upon phosphorylation. We have solved the crystal structures of the human ACK1 kinase domain in both the unphosphorylated and phosphorylated states. Comparison of these structures reveals that ACK1 adopts an activated conformation independent of phosphorylation. Furthermore, the unphosphorylated activation loop is structured, and its conformation resembles that seen in activated tyrosine kinases. In addition to the apo structure, complexes are also presented with a non-hydrolyzable nucleotide analog (adenosine 5'-(beta,gamma-methylenetriphosphate)) and with the natural product debromohymenialdisine, a general inhibitor of many protein kinases. Analysis of these structures reveals a typical kinase fold, a pre-organization into the activated conformation, and an unusual substrate-binding cleft.