Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: Structure of lck/imatinib complex
Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: Structure of lck/imatinib complex
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DOI：
10.1002/prot.21633
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发表时间：
2008-03-01
影响因子：
2.9
通讯作者：
Hare, Brian J.
中科院分区：
文献类型：
--
作者：
Jacobs, Marc D.;Caron, Paul R.;Hare, Brian J.
我们报告了一个基于两个结构元素的构象的公共人类蛋白激酶结构的聚类，激活片段和C-螺旋，揭示了三个离散的簇。一个簇包括催化活性构象中的激酶。其他簇中的每一个都包含不同的非活性构象。通常情况下，在现有的X射线结构中，激酶最多采用一种不活跃的构象，这意味着其中一种构象是许多激酶的首选构象。这一分类与几种表征良好的激酶抑制剂的选择性曲线一致。我们进一步证明了抑制物选择性曲线指导了激酶的分类。例如，伊马替尼(格列卫)对src家族中的lck的选择性抑制表明，lck的非活性构象的相对稳定性不同于其他src家族的激酶。我们报道了lck/imatinib复合体的X射线结构，证实了lck所采用的构象不同于其他结构特征的src家族激酶，而是在与imatinib的复合体中类似于激酶ABL1和Kit。我们的分类为设计小分子抑制剂开辟了新的途径。
We report a clustering of public human protein kinase structures based on the conformations of two structural elements, the activation segment and the C-helix, revealing three discrete clusters. One cluster includes kinases in catalytically active conformations. Each of the other clusters contains a distinct inactive conformation. Typically, kinases adopt at most one of the inactive conformations in available X-ray structures, implying that one of the conformations is preferred for many kinases. The classification is consistent with selectivity profiles of several well-characterized kinase inhibitors. We show further that inhibitor selectivity profiles guide kinase classification. For example, selective inhibition of lck among src-family kinases by imatinib (Gleevec) suggests that the relative stabilities of inactive conformations of lck are different from other src-family kinases. We report the X-ray structure of the lck/imatinib complex, confirming that the conformation adopted by lck is distinct from other structurally-characterized src-family kinases and instead resembles kinases abl1 and kit in complex with imatinib. Our classification creates new paths for designing small-molecule inhibitors.