Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands
Structural Analyses of Toll-like Receptor 7 Reveal Detailed RNA Sequence Specificity and Recognition Mechanism of Agonistic Ligands
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DOI：
10.1016/j.celrep.2018.11.081
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发表时间：
2018-12-18
期刊：
影响因子：
8.8
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（TLR 7）是单链RNA（ssRNA）的先天性免疫受体，在感染性疾病中具有重要作用。我们以前报道过TLR 7对鸟苷和ssRNA两种配体的协同激活。然而，特定的ssRNA序列偏好，TLR 7及其配体的详细识别模式，以及TLR 7和TLR 8选择性的分子决定因素仍然未知。在这里，我们报告TLR 7从一个大规模的晶体学研究结合多方面的方法。我们发现，连续的含尿苷的ssRNA完全或适度结合TLR 7，而单个含尿苷的ssRNA的亲和力降低。我们还揭示了配体的化学结构和它们与TLR 7的结合之间的详细关系。我们证明了工程化的TLR 8突变体改变了其对TLR 7特异性配体的反应性。最后，我们确定鸟苷2 '，3'-环磷酸（2 '，3'-cGMP）作为一个可能的内源性配体TLR 7具有更大的亲和力比鸟苷。丰富的结构信息将促进靶向TLR 7治疗的未来发展。
Toll-like receptor 7 (TLR7) is an innate immune receptor for single-stranded RNA (ssRNA) and has important roles in infectious diseases. We previously reported that TLR7 shows synergistic activation in response to two ligands, guanosine and ssRNA. However, the specific ssRNA sequence preference, detailed recognition mode of TLR7 and its ligand, and molecular determinants of TLR7 and TLR8 selectivity remain unknown. Here, we report on TLR7 from a large-scale crystallographic study combined with a multifaceted approach. We reveal that successive uridine-containing ssRNAs fully or moderately bind TLR7, whereas single uridine-containing ssRNAs have reduced affinities. We also reveal the detailed relationships between the chemical structures of ligands and their binding to TLR7. We demonstrate that an engineered TLR8 mutant alters its responsiveness to TLR7-specific ligands. Finally, we identify guanosine 2',3'-cyclic phosphate (2',3'-cGMP) as a possible endogenous ligand for TLR7 with greater affinity than guanosine. The abundant structural information will facilitate future development of treatments targeting TLR7.