Hillig Roman C, Eberspaecher Uwe, Monteclaro Felipe, Huber Martina, Nguyen Duy, Mengel Anne, Muller-Tiemann Beate, Egner Ursula
Bayer Schering Pharma AG, Research Laboratories, D-13342 Berlin, Germany.
J Mol Biol. 2007 Jun 8;369(3):735-45. doi: 10.1016/j.jmb.2007.03.004. Epub 2007 Mar 12.
The Ser/Thr protein kinase MAPKAP kinase 2 (MK2) plays a crucial role in inflammation. We determined the structure of the kinase domain of MK2 in complex with a low molecular mass inhibitor in two different crystal forms, obtained from soaking and co-crystallization. To our knowledge, these are the first structures of MK2 showing the binding mode of an inhibitor with high binding affinity (IC50 8.5 nM). The two crystal forms revealed conformational flexibility in the binding site and extend the experimental basis for rational drug design. Crystal form-1 contained one MK2 molecule per asymmetric unit. Form-2 contained 12 molecules, which arrange into two different types of MK2 trimers. One of them may serve as a model for an intermediate state during substrate phosphorylation, as each MK2 monomer places its activation segment into the substrate peptide binding groove of the trimer neighbor.
丝氨酸/苏氨酸蛋白激酶MAPKAP激酶2（MK2）在炎症中起关键作用。我们通过浸泡和共结晶获得了两种不同晶体形式的、与低分子量抑制剂结合的MK2激酶结构域结构。据我们所知，这些是首次展示具有高结合亲和力（IC50为8.5 nM）抑制剂结合模式的MK2结构。这两种晶体形式揭示了结合位点的构象灵活性，并为合理药物设计扩展了实验基础。晶体形式1每个不对称单元包含一个MK2分子。形式2包含12个分子，它们排列成两种不同类型的MK2三聚体。其中一种可能作为底物磷酸化过程中中间状态的模型，因为每个MK2单体将其激活片段置于三聚体相邻分子的底物肽结合槽中。
