p38丝裂原活化蛋白激酶吡啶基咪唑抑制剂特异性的结构基础。
The structural basis for the specificity of pyridinylimidazole inhibitors of p38 MAP kinase.
作者信息
Wilson K P, McCaffrey P G, Hsiao K, Pazhanisamy S, Galullo V, Bemis G W, Fitzgibbon M J, Caron P R, Murcko M A, Su M S
机构信息
Vertex Pharmaceuticals Incorporated 130 Waverly Street, Cambridge, MA 02139-4211, USA.
出版信息
Chem Biol. 1997 Jun;4(6):423-31. doi: 10.1016/s1074-5521(97)90194-0.
BACKGROUND
The p38 mitogen-activated protein (MAP) kinase regulates signal transduction in response to environmental stress. Pyridinylimidazole compounds are specific inhibitors of p38 MAP kinase that block the production of the cytokines interleukin-1beta and tumor necrosis factor alpha, and they are effective in animal models of arthritis, bone resorption and endotoxin shock. These compounds have been useful probes for studying the physiological functions of the p38-mediated MAP kinase pathway.
RESULTS
We report the crystal structure of a novel pyridinylimidazole compound complexed with p38 MAP kinase, and we demonstrate that this compound binds to the same site on the kinase as does ATP. Mutagenesis showed that a single residue difference between p38 MAP kinase and other MAP kinases is sufficient to confer selectivity among pyridinylimidazole compounds.
CONCLUSIONS
Our results reveal how pyridinylimidazole compounds are potent and selective inhibitors of p38 MAP kinase but not other MAP kinases. It should now be possible to design other specific inhibitors of activated p38 MAP kinase using the structure of the nonphosphorylated enzyme.
背景
p38丝裂原活化蛋白（MAP）激酶可调节对环境应激的信号转导。吡啶基咪唑化合物是p38 MAP激酶的特异性抑制剂，可阻断细胞因子白细胞介素-1β和肿瘤坏死因子α的产生，并且它们在关节炎、骨吸收和内毒素休克的动物模型中有效。这些化合物一直是研究p38介导的MAP激酶途径生理功能的有用探针。
结果
我们报道了一种与p38 MAP激酶复合的新型吡啶基咪唑化合物的晶体结构，并且我们证明该化合物与ATP一样结合在激酶的同一位点上。诱变表明，p38 MAP激酶与其他MAP激酶之间的单个残基差异足以赋予吡啶基咪唑化合物之间的选择性。
结论
我们的结果揭示了吡啶基咪唑化合物如何成为p38 MAP激酶而非其他MAP激酶的有效和选择性抑制剂。现在应该可以利用非磷酸化酶的结构设计其他活化p38 MAP激酶的特异性抑制剂。
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