Chemical and Protein Technologies, Bristol-Myers Squibb, PO Box 4000, Princeton, NJ 08543, USA.
Chem Biol Drug Des. 2011 Nov;78(5):739-48. doi: 10.1111/j.1747-0285.2011.01230.x. Epub 2011 Sep 21.
Bone marrow kinase in the X chromosome, a member of the Tec family of tyrosine kinases, plays a role in both monocyte/macrophage trafficking as well as cytokine secretion. Although the structures of Tec family kinases Bruton's tyrosine kinase and IL-2-inducible T-cell kinase are known, the crystal structures of other Tec family kinases have remained elusive. We report the X-ray crystal structures of bone marrow kinase in the X chromosome in complex with dasatinib at 2.4 Å resolution and PP2 at 1.9 Å resolution. The bone marrow kinase in the X chromosome structures reveal a typical kinase protein fold; with well-ordered protein conformation that includes an open/extended activation loop and a stabilized DFG-motif rendering the kinase in an inactive conformation. Dasatinib and PP2 bind to bone marrow kinase in the X chromosome in the ATP binding pocket and display similar binding modes to that observed in other Tec and Src protein kinases. The bone marrow kinase in the X chromosome structures identify conformational elements of the DFG-motif that could potentially be utilized to design potent and/or selective bone marrow kinase in the X chromosome inhibitors.
X 染色体中的骨髓激酶是 Tec 家族酪氨酸激酶的成员，在单核细胞/巨噬细胞迁移以及细胞因子分泌中发挥作用。尽管 Bruton 酪氨酸激酶和白细胞介素-2 诱导的 T 细胞激酶 Tec 家族激酶的结构是已知的，但其他 Tec 家族激酶的晶体结构仍然难以捉摸。我们报告了 X 染色体中的骨髓激酶与 dasatinib 在 2.4Å分辨率下和与 PP2 在 1.9Å分辨率下的 X 射线晶体结构。X 染色体中的骨髓激酶结构揭示了一种典型的激酶蛋白折叠；具有良好有序的蛋白构象，包括开放/延伸的激活环和稳定的 DFG 基序，使激酶处于非活性构象。Dasatinib 和 PP2 结合到 X 染色体中的骨髓激酶在 ATP 结合口袋中，并显示出与在其他 Tec 和Src 蛋白激酶中观察到的相似的结合模式。X 染色体中的骨髓激酶结构确定了 DFG 基序的构象元件，这些元件可能被用于设计有效的和/或选择性的 X 染色体中的骨髓激酶抑制剂。
