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首页> 外文期刊>Journal of Molecular Biology >Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors
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Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors

机译：通过选择性和多目标II型激酶抑制剂确定胶原受体DDR1抑制的结构机制

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摘要

The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9 nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and αD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a β-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.
机译：盘状蛋白域受体（DDR），DDR1和DDR2，形成由受体酪氨酸激酶的独特子家族，其被三螺旋胶原的结合激活。 DDR1和DDR2的过度信令已与各种人类疾病的进展相关联，包括纤维化，动脉粥样硬化和癌症。我们通过多目标癌症药物伊马替尼和Ponatinib以及选择性II型抑制剂DDR1-IN-1抑制这些异常受体酪氨酸激酶的抑制。 Ponatinib被鉴定为更有效的分子，其抑制DDR1和DDR2，IC50为9nm。人DDR1的共晶结构揭示了激酶结构域的DFG-OUT构象（DFG，ASP-PHE-GLY），其通过激活环和αd螺旋之间的异常盐桥稳定。在DDR1 P环中观察到对Abelson激酶（ABL）的差异，其中β-发夹取代ABL的笼状结构。因此，DDR1中的P环残基因此容纳在ATP口袋外部的抗药性。然而，伊马替尼和Ponatinib效果均致以DDR和Abl激酶，ABL P循环的疏水相互作用对于DDR1-IN-1表示不太满足其DDR1选择性的结构基础。这种抑制剂可具有在DDR1和DDR2过表达或突变的临床适应症中的应用，包括肺癌。

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  • 来源
    《Journal of Molecular Biology》 |2014年第13期|共14页
  • 作者

    CanningP.; TanL.; ChuK.; LeeS.W.; GrayN.S.; BullockA.N.;

  • 作者单位

    Structural Genomics Consortium University of Oxford Old Road Campus Roosevelt Drive Oxford OX3;

    Department of Cancer Biology Dana-Farber Cancer Institute Harvard Medical School 250 Longwood;

    Cutaneous Biology Research Center Massachusetts General Hospital Harvard Medical School;

    Cutaneous Biology Research Center Massachusetts General Hospital Harvard Medical School;

    Department of Cancer Biology Dana-Farber Cancer Institute Harvard Medical School 250 Longwood;

    Structural Genomics Consortium University of Oxford Old Road Campus Roosevelt Drive Oxford OX3;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子生物学;
  • 关键词

    crystallography; drug design; gleevec; oncology; phosphorylation;

    机译：晶体学;药物设计;Gleevec;肿瘤;磷酸化;

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