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Lipid molecules induce p38α activation via a novel molecular switch

机译:脂质分子通过新型分子开关诱导p38α活化

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p38α mitogen-activated protein kinase (MAPK) is generally activated by dual phosphorylation but has also been shown to exhibit alternative activation modes. One of these modes included a direct interaction with phosphatidylinositol ether lipid analogues (PIA) inducing p38α autoactivation and apoptosis. Perifosine, an Akt inhibitor in phase II clinical trials, also showed p38α activation properties similarly to those of PIAs. The crystal structures of p38α in complex with PIA23, PIA24 and perifosine provide insights into this unique activation mode. The activating molecules bind a unique hydrophobic binding site in the kinase C′-lobe formed in part by the MAPK insert region. In addition, there are conformational changes in the short αEF/αF loop region that acts as an activation switch, inducing autophosphorylation. Structural and biochemical characterization of the αEF/αF loop identified Trp197 as a key residue in the lipid binding and in p38α catalytic activity. The lipid binding site also accommodates hydrophobic inhibitor molecules and, thus, can serve as a novel p38α-target for specific activation or inhibition, with novel therapeutic implications.
机译:p38α丝裂原激活的蛋白激酶(MAPK)通常通过双重磷酸化激活,但也显示出其他激活模式。这些模式之一包括与磷脂酰肌醇醚脂质类似物(PIA)的直接相互作用,诱导p38α自激活和凋亡。 Perifosine是一项II期临床试验中的Akt抑制剂,也显示出与PIA相似的p38α激活特性。 p38α的晶体结构与PIA23,PIA24和periposine结合提供了洞悉这种独特激活方式的方法。活化分子结合部分由MAPK插入区形成的激酶C'-叶中的独特疏水结合位点。另外,在短的αEF/αF环区域中存在构象变化,该构象变化充当激活开关,诱导自磷酸化。 αEF/αF环的结构和生化特征表明Trp197是脂质结合和p38α催化活性中的关键残基。脂质结合位点还可以容纳疏水性抑制剂分子,因此可以用作特异性激活或抑制的新型p38α靶标,具有新的治疗意义。

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