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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3
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Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3

机译：人类EGF受体3的催化失活激酶结构域的结构分析

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摘要

The kinase domain of human epidermal growth factor receptor (HER) 3/ErbB3, a member of the EGF receptor (EGFR) family, lacks several residues that are critical for catalysis. Because catalytic activity in EGFR family members is switched on by an allosteric interaction between kinase domains in an asymmetric kinase domain dimer, HER3 might be specialized to serve as an activator of other EGFR family members. We have determined the crystal structure of the HER3 kinase domain and show that it appears to be locked into an inactive conformation that resembles that of EGFR and HER4. Although the crystal structure shows that the HER3 kinase domain binds ATP, we confirm that it is catalytically inactive but can serve as an activator of the EGFR kinase domain. The HER3 kinase domain forms a dimer in the crystal, mediated by hydrophobic contacts between the N-terminal lobes of the kinase domains. This N-lobe dimer closely resembles a dimer formed by inactive HER4 kinase domains in crystal structures determined previously, and molecular dynamics simulations suggest that the HER3 and HER4 N-lobe dimers are stable. The kinase domains of HER3 and HER4 form similar chains in their respective crystal lattices, in which N-lobe dimers are linked together by reciprocal exchange of C-terminal tails. The conservation of this tiling pattern in HER3 and HER4, which is the closest evolutionary homolog of HER3, might represent a general mechanism by which this branch of the HER receptors restricts ligand-independent formation of active het-erodimers with other members of the EGFR family.
机译：人表皮生长因子受体（HER）3 / ErbB3的激酶域是EGF受体（EGFR）家族的成员，缺少几个对催化至关重要的残基。由于不对称激酶结构域二聚体中激酶结构域之间的变构相互作用开启了EGFR家族成员的催化活性，因此HER3可能专门用作其他EGFR家族成员的激活剂。我们已经确定了HER3激酶结构域的晶体结构，并显示它似乎被锁定为类似于EGFR和HER4的无活性构象。尽管晶体结构显示HER3激酶结构域与ATP结合，但我们确认它没有催化活性，但可以用作EGFR激酶结构域的激活剂。 HER3激酶结构域在晶体中形成二聚体，由激酶结构域的N-末端叶之间的疏水接触介导。此N瓣二聚体非常类似于先前确定的晶体结构中无活性的HER4激酶结构域形成的二聚体，分子动力学模拟表明HER3和HER4 N瓣二聚体是稳定的。 HER3和HER4的激酶结构域在其各自的晶格中形成相似的链，其中N瓣二聚体通过C端尾部的相互交换而连接在一起。 HER3和HER4中最接近进化的同源基因HER3和HER4中这种重叠模式的保守性可能代表了一种通用机制，通过该机制，HER受体的这一分支限制了EGFR家族其他成员与配体无关的活性杂二聚体的形成。

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    Natalia Jura; Yibing Shan; Xiaoxian Cao; David E. Shaw; John Kuriyan;

  • 作者单位

    Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720;

    D. E. Shaw Research, New York, NY 10036;

    Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720;

    D. E. Shaw Research, New York, NY 10036 The Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032;

    Department of Molecular and Cell Biology, California Institute for Quantitative Biosciences, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720 Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 Department of Chemistry, California Institute for Quantitative Biosciences, Howard Hughes Medical Institute, University of California, Berkeley, CA 94720;

  • 收录信息 美国《科学引文索引》(SCI);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
  • 关键词

    EGFR; human epidermal growth factor receptor 3; human epidermal growth factor receptor4; receptor oligomerization;

    机译：表皮生长因子人表皮生长因子受体3;人表皮生长因子受体4;受体低聚;

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