Small-molecule inhibition of TLR8 through stabilization of its resting state.
Small-molecule inhibition of TLR8 through stabilization of its resting state.
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DOI：
10.1038/nchembio.2518
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发表时间：
2018-01
影响因子：
14.8
通讯作者：
Yin H
中科院分区：
文献类型：
--
作者：
Zhang S;Hu Z;Tanji H;Jiang S;Das N;Li J;Sakaniwa K;Jin J;Bian Y;Ohto U;Shimizu T;Yin H
内体Toll样受体（TLR 3/7/8/9）是多种病毒或细菌RNA/DNA分子模式的高度类似的传感器。然而，很少有小分子可以选择性地调节这些TLR。在这份手稿中，我们通过一种新的抑制机制鉴定了第一个人TLR 8特异性小分子拮抗剂。两种不同的TLR 8-配体复合物的晶体结构验证了TLR 8同源二聚体的蛋白质-蛋白质界面上的独特结合位点。在与这个新位点结合后，小分子配体将预先形成的TLR 8二聚体稳定在其静息状态，防止活化。作为其治疗潜力的概念证明，我们已经证明这些药物样抑制剂能够抑制各种细胞系、人原代细胞和患者标本中的TLR 8介导的促炎信号传导。这些结果不仅提出了TLR抑制剂设计的新策略，而且还揭示了这些临床上重要的免疫受体的关键机制。
Endosomal Toll-like receptors (TLR3/7/8/9) are highly analogous sensors for various viral or bacterial RNA/DNA molecular patterns. Nonetheless, few small-molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. As a proof of concept of their therapeutic potential, we have demonstrated that these drug-like inhibitors are able to suppress TLR8-mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors.
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影响因子：
8.8
作者：
Das N;Dewan V;Grace PM;Gunn RJ;Tamura R;Tzarum N;Watkins LR;Wilson IA;Yin H
通讯作者：
Yin H
影响因子：
7.3
作者：
Kokatla HP;Sil D;Malladi SS;Balakrishna R;Hermanson AR;Fox LM;Wang X;Dixit A;David SA
通讯作者：
David SA
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.3
作者：
Csakai, Adam;Smith, Christina;Yin, Hang
通讯作者：
Yin, Hang
影响因子：
32.4
作者：
Doyle, SE;Vaidya, SA;Cheng, G
通讯作者：
Cheng, G