Activation of STING by targeting a pocket in the transmembrane domain.
Activation of STING by targeting a pocket in the transmembrane domain.
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通过靶向跨膜结构域中的口袋来激活刺痛。
DOI：
10.1038/s41586-022-04559-7
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发表时间：
2022-04
期刊：
影响因子：
64.8
通讯作者：
中科院分区：
文献类型：
--
作者：
STING（干扰素基因刺激因子）是一种天然免疫中的接头蛋白，可以对抗DNA病毒或细菌。STING介导的免疫可以用于疫苗或癌症免疫疗法。STING是位于内质网（ER）或高尔基体中的跨膜（TM）二聚体蛋白。STING通过其细胞质配体结合结构域（LBD）与由DNA传感器环GMP-AMP（cGAMP）合酶（cGAS）或入侵细菌产生的环二核苷酸结合而被激活。环状二核苷酸诱导STING LBD的构象变化，导致STING的高阶寡聚化，这对于触发下游信号传导途径是必需的。然而，cGAMP诱导的STING寡聚体看起来很弱，并且没有被解析到高分辨率，阻碍了对激活机制的理解。在这里，我们表明小分子激动剂化合物53（C53）通过与cGAMP正交的机制促进人类STING寡聚化和激活。我们确定了与C53和cGAMP结合的STING的cryo-EM结构，揭示了通过并排包装形成的具有卷曲整体形状的稳定低聚物。令人惊讶的是，C53结合STING二聚体的两个亚基之间的STING TM结构域（TMD）中的隐蔽口袋。这种结合诱导二聚体中TM螺旋向外移位，促进它们进行二聚体间相互作用以介导高阶寡聚体的形成。我们的功能分析表明，cGAMP和C53一起诱导STING的更强激活。
STING (Stimulator of interferon genes) is an adaptor protein in innate immunity against DNA viruses or bacteria. STING-mediated immunity could be harnessed for vaccines or cancer immuno-therapies. STING is a transmembrane (TM) dimeric protein located in the endoplasmic reticulon (ER) or Golgi. STING is activated by binding of its cytoplasmic ligand-binding domain (LBD) to cyclic dinucleotides, produced by the DNA-sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS) or invading bacteria. Cyclic dinucleotides induce a conformational change to the STING LBD, leading to high-order oligomerization of STING that is essential for triggering the downstream signaling pathways. However, the cGAMP-induced STING oligomers appeared weak and have not been resolved to high resolution, hampering the understanding of the activation mechanism. Here we show that a small molecular agonist, compound 53 (C53), promotes human STING oligomerization and activation through a mechanism orthogonal to that of cGAMP. We determined a cryo-EM structure of STING bound to both C53 and cGAMP, revealing a stable oligomer formed by side-by-side packing with a curled overall shape. Surprisingly, C53 binds to a cryptic pocket in the STING TM domain (TMD), between the two subunits of the STING dimer. This binding induces outward shifts of TM helices in the dimer, promoting them to make inter-dimer interactions to mediate the formation of the high-order oligomer. Our functional analyses show that cGAMP and C53 together induce stronger activation of STING.
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影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A
影响因子：
64.8
作者：
Dou Z;Ghosh K;Vizioli MG;Zhu J;Sen P;Wangensteen KJ;Simithy J;Lan Y;Lin Y;Zhou Z;Capell BC;Xu C;Xu M;Kieckhaefer JE;Jiang T;Shoshkes-Carmel M;Tanim KMAA;Barber GN;Seykora JT;Millar SE;Kaestner KH;Garcia BA;Adams PD;Berger SL
通讯作者：
Berger SL
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.8
作者：
Ernst AM;Syed SA;Zaki O;Bottanelli F;Zheng H;Hacke M;Xi Z;Rivera-Molina F;Graham M;Rebane AA;Björkholm P;Baddeley D;Toomre D;Pincet F;Rothman JE
通讯作者：
Rothman JE