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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hidden dynamic allostery in a PDZ domain
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Hidden dynamic allostery in a PDZ domain

机译：PDZ域中的隐藏动态变构

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摘要

Structure-function relationships in proteins are predicated on the spatial proximity of noncovalently interacting groups of atoms. Thus, structural elements located away from a protein's active site are typically presumed to serve a stabilizing or scaffolding role for the larger structure. Here we report a functional role for a distal structural element in a PDZ domain, even though it is not required to maintain PDZ structure. The third PDZ domain from PSD-95/SAP90 (PDZ3) has an unusual additional third alpha helix (α3) that packs in contiguous fashion against the globular domain. Although α3 lies outside the active site and does not make direct contact with C-terminal peptide ligand, removal of α3 reduces ligand affinity by 21-fold. Further investigation revealed that the difference in binding free energies between the full-length and truncated constructs is predominantly entropic in nature and that without α3, picosecond-nanosecond side-chain dynamics are enhanced throughout the domain, as determined by ~2H methyl NMR relaxation. Thus, the distal modulation of binding function appears to occur via a delocalized conformational entropy mechanism. Without removal of α3 and characterization of side-chain dynamics, this dynamic allostery would have gone unnoticed. Moreover, what appeared at first to be an artificial modification of PDZ3 has been corroborated by experimentally verified phosphor-ylation of α3, revealing a tangible biological mechanism for this novel regulatory scheme. This hidden dynamic allostery raises the possibility of as-yet unidentified or untapped allosteric regulation in this PDZ domain and is a very clear example of function arising from dynamics rather than from structure.
机译：蛋白质中的结构-功能关系取决于非共价相互作用的原子团的空间接近性。因此，通常认为远离蛋白质活性位点的结构元件对较大结构起稳定或支架作用。在这里，我们报告了P​​DZ域中远端结构元素的功能作用，即使不需要维持PDZ结构也是如此。 PSD-95 / SAP90中的第三个PDZ域（PDZ3）具有一个不寻常的附加第三alpha螺旋（α3），它以连续的方式堆积在球形域上。尽管α3位于活性位点之外，并且不与C端肽配体直接接触，但是去除α3会使配体亲和力降低21倍。进一步的研究表明，全长结构和截短结构之间的结合自由能的差异主要是熵，而没有α3的情况下，皮秒级至纳秒级侧链动力学在整个结构域中均得到增强，这由〜2H甲基NMR弛豫确定。因此，结合功能的远端调节似乎是通过离域构象熵机制发生的。如果不去除α3和表征侧链动力学，这种动态变构就不会引起注意。此外，通过实验验证的α3的磷酸化，已经证实了最初看起来是PDZ3的人工修饰，从而揭示了这种新型调控方案的切实生物学机制。这种隐藏的动态变构，增加了在该PDZ域中尚未确定或尚未开发的变构调节的可能性，并且是动态而不是结构产生的功能的非常清楚的例子。

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  • 作者

    Chad M. Petit; Jun Zhang; Paul J. Sapienza; Ernesto J. Fuentes; Andrew L. Lee;

  • 作者单位

    Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy,University of North Carolina, Chapel Hill, NC 27599;

    Department of Biochemistry and Biophysics, School of Medicine,University of North Carolina, Chapel Hill, NC 27599;

    Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy,University of North Carolina, Chapel Hill, NC 27599;

    Department of Biochemistry, University of Iowa, Iowa City, IA 52242;

    Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy,University of North Carolina, Chapel Hill, NC 27599 Department of Biochemistry and Biophysics, School of Medicine,University of North Carolina, Chapel Hill, NC 27599;

  • 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

    NMR; PSD-95; spin relaxation; entropy;

    机译：NMR;PSD-95;旋转放松熵;

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