PharmAxess, Inc., 3-9-12, Matsubara-cho, Akishima, Tokyo 196-8666, Japan.
J Biochem. 2012 May;151(5):541-9. doi: 10.1093/jb/mvs023. Epub 2012 Mar 1.
Mitogen-activated protein kinase kinase 6 (MAP2K6) plays a crucial role in the p38 MAP kinase signal cascade that regulates various stress-induced responses and is associated with pathological conditions. The crystal structure of human non-phosphorylated MAP2K6 (npMAP2K6) complexed with an ATP analogue was determined at 2.6 Å resolution and represents an auto-inhibition state of MAP2K6. Three characteristics of short α-helices configured in the activation loop region, termed activation helices (AH1, AH2 and AH3), are important in controlling the auto-inhibition mechanism. AH1 displaces the αC-helix, a component essential for forming the active configuration, away from the active site. AH1 and AH2 were found to enclose the γ-phosphate, the leaving group of ATP. A comparison with the related enzymes, MAP2K1 and MAP2K4 reveals that MAP2K6 has the unique auto-inhibition mechanism mediated by the three activation helices.
丝裂原活化蛋白激酶激酶 6（MAP2K6）在调节各种应激诱导反应的 p38 MAP 激酶信号级联中发挥着关键作用，并且与病理状况有关。与人非磷酸化 MAP2K6（npMAP2K6）与 ATP 类似物复合物的晶体结构在 2.6 Å 分辨率下确定，代表了 MAP2K6 的自动抑制状态。在激活环区域中配置的三个短α-螺旋的特征，称为激活螺旋（AH1、AH2 和 AH3），在控制自动抑制机制方面非常重要。AH1 使αC-螺旋移位，αC-螺旋是形成活性构型所必需的成分，远离活性部位。发现 AH1 和 AH2 包围γ-磷酸，即 ATP 的离去基团。与相关酶 MAP2K1 和 MAP2K4 的比较表明，MAP2K6 具有由三个激活螺旋介导的独特的自动抑制机制。
