Structural analysis reveals TLR7 dynamics underlying antagonism.
Structural analysis reveals TLR7 dynamics underlying antagonism.
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DOI：
10.1038/s41467-020-19025-z
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发表时间：
2020-10-15
影响因子：
16.6
通讯作者：
Shimizu T
中科院分区：
文献类型：
--
作者：
Tojo S;Zhang Z;Matsui H;Tahara M;Ikeguchi M;Kochi M;Kamada M;Shigematsu H;Tsutsumi A;Adachi N;Shibata T;Yamamoto M;Kikkawa M;Senda T;Isobe Y;Ohto U;Shimizu T
Toll-like receptor 7 (TLR7) recognizes both microbial and endogenous RNAs and nucleosides. Aberrant activation of TLR7 has been implicated in several autoimmune diseases including systemic lupus erythematosus (SLE). Here, by modifying potent TLR7 agonists, we develop a series of TLR7-specific antagonists as promising therapeutic agents for SLE. These compounds protect mice against lethal autoimmunity. Combining crystallography and cryo-electron microscopy, we identify the open conformation of the receptor and reveal the structural equilibrium between open and closed conformations that underlies TLR7 antagonism, as well as the detailed mechanism by which TLR7-specific antagonists bind to their binding pocket in TLR7. Our work provides small-molecule TLR7-specific antagonists and suggests the TLR7-targeting strategy for treating autoimmune diseases. A series of Toll-like receptor 7 (TLR7)-specific antagonists and extensive structural analysis reveal the open conformation of the receptor and the structural basis of TLR7 antagonism. One of the compounds shows efficacy in treating mouse model of systemic lupus erythematosus.
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影响因子：
48
作者：
Kucukelbir, Alp;Sigworth, Fred J.;Tagare, Hemant D.
通讯作者：
Tagare, Hemant D.
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
DOI：
10.1073/pnas.1314121111
发表时间：
2014-01-28
影响因子：
11.1
作者：
Desnues, Benoit;Macedo, Amanda Beatriz;Alexopoulou, Lena
通讯作者：
Alexopoulou, Lena
影响因子：
6.4
作者：
Koga-Yamakawa, Erina;Dovedi, Simon J.;Harada, Hideyuki
通讯作者：
Harada, Hideyuki
影响因子：
21.3
作者：
Linares, Laetitia K.;Kiernan, Rosemary;Benkirane, Monsef
通讯作者：
Benkirane, Monsef