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Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface

机译：通过将MIG6与激活的激酶结构域界面结合来抑制EGF受体

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摘要

Members of the epidermal growth factor receptor family (EGFR/ ERBB1, ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are key targets for inhibition in cancer therapy. Critical for activation is the formation of an asymmetric dimer by the intracellular kinase domains, in which the carboxy-terminal lobe (Clobe) of one kinase domain induces an active conformation in the other. The cytoplasmic protein MIG6 (mitogen-induced gene 6; also known as ERRFI1) interacts with and inhibits the kinase domains of EGFR and ERBB2 (refs 3-5). Crystal structures of complexes between the EGFR kinase domain and a fragment of MIG6 show that a ～25-residue epitope (segment 1) from MIG6 binds to the distal surface of the C lobe of the kinase domain. Biochemical and cell-based analyses confirm that this interaction contributes to EGFR inhibition by blocking the formation of the activating dimer interface. A longer MIG6 peptide that is extended C terminal to segment 1 has increased potency as an inhibitor of the activated EGFR kinase domain, while retaining a critical dependence on segment 1. We show that signalling by EGFR molecules that contain constitu-tively active kinase domains still requires formation of the asymmetric dimer, underscoring the importance of dimer interface blockage in MIG6-mediated inhibition.
机译：表皮生长因子受体家族的成员（EGFR / ERBB1，ERBB2 / HER2，ERBB3 / HER3和ERBB4 / HER4）是抑制癌症治疗的关键靶标。激活的关键是细胞内激酶结构域形成不对称二聚体，其中一个激酶结构域的羧基末端叶（Clobe）在另一个激酶结构域中诱导活性构象。细胞质蛋白MIG6（促分裂原诱导的基因6；也称为ERRFI1）与EGFR和ERBB2的激酶结构域相互作用并抑制它们（参考文献3-5）。 EGFR激酶结构域和MIG6片段之间的复合物的晶体结构表明，MIG6的〜25个残基表位（片段1）与激酶结构域C瓣的远端表面结合。生化和基于细胞的分析证实，这种相互作用通过阻止激活二聚体界面的形成而有助于EGFR抑制。 C末端延伸至区段1的较长MIG6肽作为活化的EGFR激酶结构域的抑制剂具有增强的功效，同时保留了对区段1的关键依赖性。需要形成不对称的二聚体，强调了在MIG6介导的抑制中二聚体界面阻断的重要性。

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  • 来源
    《Nature》 |2007年第7170期|741-744|共4页
  • 作者

    Xuewu Zhang; Kerry A. Pickin; Ron Bose; Natalia Jura; Philip A. Cole; John Kuriyan;

  • 作者单位

    Department of Molecular and Cell Biology, and Department of Chemistry, and Howard Hughes Medical Institute, California Institute for Quantitative Sciences, University of California, Berkeley, California 94720, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自然科学总论;
  • 关键词

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