Article
作者: Cho, Charles Y ; McWhirter, Sarah M ; Bai, Xiao-Chen ; Ross, Nathan T ; Patel, Sejal J ; Tallarico, John A ; Digan, Mary Ellen ; Yu, Gary ; Henault, Martin ; Tutter, Antonin ; Canham, Stephen M ; Wang, Yuan ; Feng, Yan ; Zheng, Lianxing ; Sivick, Kelsey E ; Mao, Xiaohong ; Michaud, Gregory A ; Li, Jie ; Brittain, Scott M ; Chen, Christine H ; Liu, Guoxun ; Nicholson, Thomas B ; Pham, Helen T ; Wu, Hua ; Zhang, Xuewu ; McKenna, Jeffery M ; Jenkins, Jeremy L ; Tria, George S ; Chen, Yu ; Hornak, Viktor ; Chen, Lihao ; Jain, Rishi K ; Schirle, Markus ; Miller, Howard R ; Broom, Wendy
Abstract: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.