Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine.
Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine.
复制标题
抑制剂十字孢菌素结合的 MAP3K TAO2 激酶结构域的晶体结构。
DOI：
10.1111/j.1745-7270.2006.00173.x
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发表时间：
2006
影响因子：
3.7
通讯作者：
Goldsmith,ElizabethJ
中科院分区：
文献类型：
--
作者：
Zhou,Tian-Jun;Sun,Li-Guang;Gao,Yan;Goldsmith,ElizabethJ
丝裂原活化蛋白激酶（MAPK）信号转导途径在真核细胞中普遍存在，它将信号从细胞表面传递到细胞核，控制着多种细胞程序。MAPK被MAPK激酶[MAP2Ks或MAP/细胞外信号调节激酶（ERK）激酶（MEK）]激活，而MEK又被MAPK激酶（MAP3Ks）激活。TAO2是一种MAP3K水平的激酶，可以激活MAP2Ks， MEK3和MEK6来激活p38 MAPKs。由于p38 MAPKs是炎症细胞因子表达的关键调节因子，它们似乎与哮喘和自身免疫等人类疾病有关。作为p38s的上游激活剂，TAO2是一个潜在的药物靶点。本文报道了TAO2激酶活性结构域与staurosporine复合物的晶体结构，staurosporine是一种广谱蛋白激酶抑制剂，抑制TAO2的ic50为3 μM。该结构表明，staurosporine占据了TAO2中ATP腺苷结合的位置，该抑制剂的结合模仿了ATP结合的许多特征。极性和非极性相互作用都有助于酶抑制剂的识别。Staurosporine诱导围绕抑制剂分子的TAO2残基的构象变化，但在激酶中引起非常有限的全局变化。该结构提供了TAO2 - staurosporine相互作用的原子细节，并解释了staurosporine对TAO2相对较低的效力。这里提出的结构应该有助于设计特异性的TAO2和相关激酶抑制剂。编辑：丁建平
Mitogen‐activated protein kinase (MAPK) signal transduction pathways are ubiquitous in eukaryotic cells, which transfer signals from the cell surface to the nucleus, controlling multiple cellular programs. MAPKs are activated by MAPK kinases [MAP2Ks or MAP/extracellular signal‐regulated kinase (ERK) kinases (MEK)], which in turn are activated by MAPK kinase kinases (MAP3Ks). TAO2 is a MAP3K level kinase that activates the MAP2Ks MEK3 and MEK6 to activate p38 MAPKs. Because p38 MAPKs are key regulators of expression of inflammatory cytokines, they appear to be involved in human diseases such as asthma and autoimmunity. As an upstream activator of p38s, TAO2 represents a potential drug target. Here we report the crystal structure of active TAO2 kinase domain in complex with staurosporine, a broad‐range protein kinase inhibitor that inhibits TAO2 with an IC50of 3 μM. The structure reveals that staurosporine occupies the position where the adenosine of ATP binds in TAO2, and the binding of the inhibitor mimics many features of ATP binding. Both polar and nonpolar interactions contribute to the enzyme‐inhibitor recognition. Staurosporine induces conformational changes in TAO2 residues that surround the inhibitor molecule, but causes very limited global changes in the kinase. The structure provides atomic details for TAO2‐staurosporine interactions, and explains the relatively low potency of staurosporine against TAO2. The structure presented here should aid in the design of inhibitors specific to TAO2 and related kinases.Edited byJian‐Ping DING