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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Binary complex crystal structure of DNA polymerase β reveals multiple conformations of the templating 8-oxoguanine lesion
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Binary complex crystal structure of DNA polymerase β reveals multiple conformations of the templating 8-oxoguanine lesion

机译：DNA聚合酶β的二元复合晶体结构揭示了模板化的8-氧鸟嘌呤损伤的多个构象

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摘要

Oxidation of genomic DNA forms the guanine lesion 7,8-dihydro-8-oxoguanine (8-oxoG). When in the template base position during DNA synthesis the 8-oxoG lesion has dual coding potential by virtue of its anti- and syn-conformations, base pairing with cytosine and adenine, respectively. This impacts mutagenesis, because insertion of adenine opposite template 8-oxoG can result in a G to T transversion. DNA polymerases vary by orders of magnitude in their preferences for mutagenic vs. error-free 8-oxoG lesion bypass. Yet, the structural basis for lesion bypass specificity is not well understood. The DNA base excision repair enzyme DNA polymerase (pol) β is presented with gap-filling synthesis opposite 8-oxoG during repair and has similar insertion efficiencies for dCTP and dATP. We report the structure of pol β in binary complex with template 8-oxoG in a base excision repair substrate. The structure reveals both the syn- and anti-conformations of template 8-oxoG in the confines of the polymerase active site, consistent with the dual coding observed kinetically for this enzyme. A ternary complex structure of pol P with the syn-8-oxoG:anti-A Hoogsteen base pair in the closed fully assembled preinsertion active site is also reported. The syn-conformation of 8-oxoG is stabilized by minor groove hydrogen bonding between the side chain of Arg283 and 08 of 8-oxoG. An adjustment in the position of the phosphodiester backbone 5-phosphate enables 8-oxoG to adopt the syn-conformation.
机译：基因组DNA的氧化形成鸟嘌呤病变7,8-dihydro-8-oxoguanine（8-oxoG）。当在DNA合成过程中处于模板碱基位置时，8-oxoG病变凭借其反构和同构，分别与胞嘧啶和腺嘌呤碱基配对而具有双重编码潜能。这会影响诱变，因为与模板8-oxoG相对的腺嘌呤插入会导致G到T的转化。 DNA聚合酶在诱变vs.无错8-oxoG病变旁路中的偏好差异很大。然而，对于病变旁路特异性的结构基础还没有很好的理解。 DNA碱基切除修复酶DNA聚合酶（pol）β在修复过程中以与8-oxoG相反的缺口填充合成形式出现，对dCTP和dATP具有相似的插入效率。我们报告了在基础切除修复基质中具有模板8-oxoG的二元复合物中polβ的结构。该结构揭示了聚合酶活性位点范围内模板8-oxoG的顺式和反式构象，与该酶在动力学上观察到的双重编码一致。还报道了在封闭的完全组装的预插入活性位点中pol P与syn-8-oxoG：anti-A Hoogsteen碱基对的三元复合结构。 8-oxoG的顺式构象通过Arg283侧链与8-oxoG的08之间的小沟氢键得以稳定。磷酸二酯主链5-磷酸酯的位置的调节使8-oxoG采用顺式构象。

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    Vinod K. Batra; David D. Shock; William A. Beard; Charles E. McKenna; Samuel H. Wilson;

  • 作者单位

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709-2233;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709-2233;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709-2233;

    Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744;

    Laboratory of Structural Biology, National Institute of Environmental Health Sciences, National Institutes of Health, P.O. Box 12233, Research Triangle Park, NC 27709-2233;

  • 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
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  • 关键词

    oxidative DNA lesion; X-ray crystallography;

    机译：氧化性DNA损伤X射线晶体学;

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