Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA
Structural Analysis Reveals that Toll-like Receptor 7 Is a Dual Receptor for Guanosine and Single-Stranded RNA
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DOI：
10.1016/j.immuni.2016.09.011
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发表时间：
2016-10-18
期刊：
影响因子：
32.4
通讯作者：
Shimizu, Toshiyuki
中科院分区：
文献类型：
--
作者：
Zhang, Zhikuan;Ohto, Umeharu;Shimizu, Toshiyuki
toll样受体7 （TLR7）是先天免疫中的单链RNA （ssRNA）传感器，也对鸟苷和化学配体（如咪唑喹啉化合物）有反应。然而，TLR7被这些配体激活的机制在很大程度上仍然未知。在这里，我们生成了三种TLR7配合物的晶体结构，发现它们都形成了一个具有两个配体结合位点的活化m型二聚体。TLR7和TLR8中保守的第一个位点用于激活必需的小配体结合。与TLR8在空间上不同的第二个位点被用于ssrna结合，增强了第一个位点配体的亲和力。第一个位点优先识别鸟苷，第二个位点特异性结合ssRNA中的尿苷部分。我们的结构、生化和诱变研究表明，TLR7是鸟苷和尿苷ssRNA的双重受体。我们的发现对于理解TLR7的功能以及TLR7激活的治疗性操作具有重要意义。
Toll-like receptor 7 (TLR7) is a single-stranded RNA (ssRNA) sensor in innate immunity and also responds to guanosine and chemical ligands, such as imidazoquinoline compounds. However, TLR7 activation mechanism by these ligands remain largely unknown. Here, we generated crystal structures of three TLR7 complexes, and found that all formed an activated m-shaped dimer with two ligand-binding sites. The first site conserved in TLR7 and TLR8 was used for small ligand-binding essential for its activation. The second site spatially distinct from that of TLR8 was used for a ssRNA-binding that enhanced the affinity of the first-site ligands. The first site preferentially recognized guanosine and the second site specifically bound to uridine moieties in ssRNA. Our structural, biochemical, and mutagenesis studies indicated that TLR7 is a dual receptor for guanosine and uridine-containing ssRNA. Our findings have important implications for understanding of TLR7 function, as well as for therapeutic manipulation of TLR7 activation.