通过分子胶状化合物激活人类 STING。
Activation of human STING by a molecular glue-like compound.
发表日期：2023 Oct 12
作者：
Jie Li, Stephen M Canham, Hua Wu, Martin Henault, Lihao Chen, Guoxun Liu, Yu Chen, Gary Yu, Howard R Miller, Viktor Hornak, Scott M Brittain, Gregory A Michaud, Antonin Tutter, Wendy Broom, Mary Ellen Digan, Sarah M McWhirter, Kelsey E Sivick, Helen T Pham, Christine H Chen, George S Tria, Jeffery M McKenna, Markus Schirle, Xiaohong Mao, Thomas B Nicholson, Yuan Wang, Jeremy L Jenkins, Rishi K Jain, John A Tallarico, Sejal J Patel, Lianxing Zheng, Nathan T Ross, Charles Y Cho, Xuewu Zhang, Xiao-Chen Bai, Yan Feng
来源：
Nature Chemical Biology
摘要：
干扰素基因刺激物 (STING) 是一种二聚体跨膜接头蛋白，在人类对感染的先天免疫反应中发挥着关键作用，并因其抗肿瘤活性而被用于治疗。 STING 的激活需要其高阶寡聚化，这可以通过内源配体 cGAMP 与胞质配体结合域的结合来诱导。在这里，我们通过一类化合物的功能筛选报告了这一发现，该化合物名为 NVS-STG，可激活人类 STING。我们的冷冻电镜结构表明，NVS-STG2 通过与相邻 STING 二聚体的跨膜结构域之间的口袋结合，诱导人类 STING 的高阶寡聚化，有效地充当分子胶。我们的功能分析表明，NVS-STG2 可以在细胞中引发有效的 STING 介导的免疫反应，并在动物模型中引发抗肿瘤活性。© 2023。作者。
Stimulator of interferon genes (STING) is a dimeric transmembrane adapter protein that plays a key role in the human innate immune response to infection and has been therapeutically exploited for its antitumor activity. The activation of STING requires its high-order oligomerization, which could be induced by binding of the endogenous ligand, cGAMP, to the cytosolic ligand-binding domain. Here we report the discovery through functional screens of a class of compounds, named NVS-STGs, that activate human STING. Our cryo-EM structures show that NVS-STG2 induces the high-order oligomerization of human STING by binding to a pocket between the transmembrane domains of the neighboring STING dimers, effectively acting as a molecular glue. Our functional assays showed that NVS-STG2 could elicit potent STING-mediated immune responses in cells and antitumor activities in animal models.© 2023. The Author(s).