Structures of human MST3 kinase in complex with adenine, ADP and Mn2+
Structures of human MST3 kinase in complex with adenine, ADP and Mn2+
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DOI：
10.1107/s0907444909047507
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发表时间：
2010-02-01
期刊：
影响因子：
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通讯作者：
Wang, Andrew H. -J.
中科院分区：
文献类型：
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作者：
Ko, Tzu-Ping;Jeng, Wen-Yih;Wang, Andrew H. -J.
MST家族是哺乳动物丝氨酸/苏氨酸激酶的一个亚类，与酵母不育-20蛋白相关，参与调节细胞的生长和转化。MST3蛋白含有一个300个残基的催化结构域和一个130个残基的调控结构域，可被caspase切割并被自身磷酸化激活，从而促进细胞凋亡。本文介绍了MST3催化域的五种晶体结构，包括与ADP和锰的络合物，酶所偏好的独特的辅因子，以及与腺嘌呤的络合物。与其他蛋白激酶类似，MST3的催化结构域折叠成两个叶：较小的N叶形成核苷酸结合部位，较大的C叶识别多肽底物。结合的ADP和Mn2+离子被一个富含甘氨酸的环覆盖，并被Asn149和Asp162固定在适当的位置。在MST3-腺嘌呤复合体中观察到不同的配基取向。在激活环中，Thr178的侧链被磷酸化，并被Arg143和Arg176夹在中间。将该结构与其他类似的激酶结构进行比较，显示环路旋转180度，导致酶的激活。明确的蛋白质-配体相互作用也为设计有效的抑制剂提供了有用的信息。
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 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.