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Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9

机译：CpG的结构基础和Toll样受体9抑制性DNA识别

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摘要

Innate immunity serves as the first line of defence against invading pathogens such as bacteria and viruses'. Toll-like receptors (TLRs) are examples of innate immune receptors, which sense specific molecular patterns from pathogens and activate immune responses'. TLR9 recognizes bacterial and viral DNA containing the cytosinephosphate-guanine (CpG) dideoxynucleotide moth". The molecular basis by which CpG-containing DNA (CpG-DNA) elicits immunostimulatory activity via TLR9 remains to be elucidated. Here we show the crystal structures of three forms of TLR9: unliganded, bound to agonistic CpG-DNA, and bound to inhibitory DNA (iDNA). AgonisticCpG-DNA-bound TLR9 formed a symmetric TLR9-CpG-DNA complex with 2:2 stoichiometry, whereas iDNA-bound TLR9 was a monomer. CpG-DNA was recognized by both protomers in the dimer, in particular by the amino-terminal fragment (LRRNT-LRR10) from one protomer and the carboxy-terminal fragment (LRR2O-LRR22) from the other. The iDNA, which formed a stem-loop structure suitable for binding by intramolecular base pairing, bound to the concave surface from LRR2-LRR 1 O. This structure serves as an important basis for improving our understanding of the functional mechanisms of TLR9.
机译：先天免疫是抵御​​细菌和病毒等病原体入侵的第一道防线。 Toll样受体（TLR）是先天性免疫受体的例子，它们可以感知病原体的特定分子模式并激活免疫反应。 TLR9识别含有胞嘧啶磷酸鸟嘌呤（CpG）双脱氧核苷酸蛾的细菌和病毒DNA。“含有CpG的DNA（CpG-DNA）通过TLR9引发免疫刺激活性的分子基础尚待阐明。在这里，我们展示了三种晶体的结构TLR9的形式：未配体，与激动性CpG-DNA结合，并与抑制性DNA（iDNA）结合，与CgG-DNA结合的AgonisticCpG-DNA形成了化学计量比为2：2的对称TLR9-CpG-DNA复合物，而与iDNA结合的TLR9是CpG-DNA被二聚体中的两个启动子识别，特别是被一个启动子的氨基末端片段（LRRNT-LRR10）和另一个启动子的羧基末端片段（LRR2O-LRR22）识别。适于通过分子内碱基配对结合的茎环结构，结合到LRR2-LRR 1 O的凹表面上。该结构为增进我们对TLR9的功能机理的理解提供了重要基础。

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  • 来源
    《Nature》 |2015年第7549期|702-705|共4页
  • 作者

    Ohto Umeharu; Shibata Takuma; Tanji Hiromi; Ishida Hanako; Krayukhina Elena; Uchiyama Susumu; Miyake Kensuke; Shimizu Toshiyuki;

  • 作者单位

    Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan;

    Univ Tokyo, Dept Microbiol & Immunol, Ctr Expt Med & Syst Biol, Div Innate Immun,Lab Innate Immun,Inst Med Sci,Mi, Tokyo 1088639, Japan|Japan Sci & Technol Agcy JST, CREST, Kawaguchi, Saitama 3320012, Japan;

    Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan;

    Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan;

    Osaka Univ, Grad Sch Engn, Suita, Osaka 5650871, Japan|U Med Corp, Suita, Osaka 5650871, Japan;

    Osaka Univ, Grad Sch Engn, Suita, Osaka 5650871, Japan;

    Univ Tokyo, Dept Microbiol & Immunol, Ctr Expt Med & Syst Biol, Div Innate Immun,Lab Innate Immun,Inst Med Sci,Mi, Tokyo 1088639, Japan;

    Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan|Japan Sci & Technol Agcy JST, CREST, Kawaguchi, Saitama 3320012, Japan;

  • 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);
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