Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases
Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases
复制标题
DOI：
10.1002/pro.321
复制
发表时间：
2010-03-01
期刊：
影响因子：
8
通讯作者：
Silvian, Laura F.
中科院分区：
文献类型：
--
作者：
Marcotte, Douglas J.;Liu, Yu-Ting;Silvian, Laura F.
布鲁顿酪氨酸激酶（BTK）是TEC激酶家族的成员，在B细胞成熟和肥大细胞活化中发挥着至关重要的作用。尽管已知未磷酸化的小鼠BTK激酶结构域和人ITK的未磷酸化和磷酸化的激酶结构域的结构，但由于缺乏高分辨率的配体结合的BTK结构，因此阻碍了对BTK抑制剂的激酶选择性谱的理解。在这里，我们报告了在1.9埃分辨率下与达沙替尼（BMS-354825）结合或在1.6埃分辨率下与4-氨基-5-（4-苯氧基苯基）-7H-吡咯并嘧啶-7-基-环戊烷结合的人BTK激酶结构域的晶体结构。该数据提供了与靶向BTK和TEC家族非受体酪氨酸激酶的小分子抑制剂的开发相关的信息。TEC和Src家族的激酶附近的Trp-Glu-Ile基序在N-末端区域的激酶结构域的结构差异的分析表明TEC家族成员的调节机制。
Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 angstrom resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin-7-yl-cyclopentane at 1.6 angstrom resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.