Fujino Aiko, Fukushima Kei, Namiki Naoko, Kosugi Tomomi, Takimoto-Kamimura Midori
Teijin Institute for Biomedical Research, Japan.
Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):80-7. doi: 10.1107/S0907444909046411. Epub 2009 Dec 21.
Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAP-K2 or MK2) is a Ser/Thr kinase from the p38 mitogen-activated protein kinase signalling pathway and plays an important role in inflammatory diseases. The crystal structure of the complex of human MK2 (residues 41-364) with the potent MK2 inhibitor TEI-I01800 (pK(i) = 6.9) was determined at 2.9 A resolution. The MK2 structure in the MK2-TEI-I01800 complex is composed of two domains, as observed for other Ser/Thr kinases; however, the Gly-rich loop in the N-terminal domain forms an alpha-helix structure and not a beta-sheet. TEI-I01800 binds to the ATP-binding site as well as near the substrate-binding site of MK2. Both TEI-I01800 molecules have a nonplanar conformation that differs from those of other MK2 inhibitors deposited in the Protein Data Bank. The MK2-TEI-I01800 complex structure is the first active MK2 with an alpha-helical Gly-rich loop and TEI-I01800 regulates the secondary structure of the Gly-rich loop.
丝裂原活化蛋白激酶激活的蛋白激酶2（MAPKAP-K2或MK2）是p38丝裂原活化蛋白激酶信号通路中的一种丝氨酸/苏氨酸激酶，在炎症性疾病中起重要作用。已在2.9埃分辨率下确定了人MK2（第41-364位残基）与强效MK2抑制剂TEI-I01800（pK(i)=6.9）复合物的晶体结构。与其他丝氨酸/苏氨酸激酶一样，MK2-TEI-I01800复合物中的MK2结构由两个结构域组成；然而，N端结构域中富含甘氨酸的环形成的是α螺旋结构而非β折叠。TEI-I01800与MK2的ATP结合位点以及底物结合位点附近结合。两个TEI-I01800分子均具有非平面构象，这与蛋白质数据库中存放的其他MK2抑制剂不同。MK2-TEI-I01800复合物结构是首个具有α螺旋富含甘氨酸环的活性MK2，且TEI-I01800可调节富含甘氨酸环的二级结构。
