Xie Zuoquan, Wang Zhen, Fan Fengying, Zhou Jinpei, Hu Zhaoxue, Wang Qingxia, Wang Xiyuan, Zeng Qingzhong, Zhang Yan, Qiu Jiaxuan, Zhou Xiaoqian, Xu Hui, Bai Hudagula, Zhan Zhengsheng, Ding Jian, Zhang Huibin, Duan Wenhu, Yu Xuekui, Geng Meiyu
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Cryo-Electron Microscopy Research Center & The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Cell Discov. 2022 Dec 13;8(1):133. doi: 10.1038/s41421-022-00481-4.
Stimulator of interferon gene (STING) is increasingly exploited for the potential in cancer immunotherapy, yet its mechanism of activation remains not fully understood. Herein, we designed a novel STING agonist, designated as HB3089 that exhibits robust and durable anti-tumor activity in tumor models across various cancer types. Cryo-EM analysis reveals that HB3089-bound human STING has structural changes similar to that of the STING mutant V147L, a constitutively activated mutant identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). Both structures highlight the conformational changes of the transmembrane domain (TMD), but without the 180°-rotation of the ligand binding domain (LBD) previously shown to be required for STING activation. Further structure-based functional analysis confirmed a new STING activation mode shared by the agonist and the SAVI-related mutation, in which the connector linking the LBD and the TMD senses the activation signal and controls the conformational changes of the LBD and the TMD for STING activation. Together, our findings lead to a new working model for STING activation and open a new avenue for the rationale design of STING-targeted therapies either for cancer or autoimmune disorders.
干扰素基因刺激因子（STING）在癌症免疫治疗中的潜力正越来越多地得到开发利用，但其激活机制仍未完全明确。在此，我们设计了一种新型的STING激动剂，命名为HB3089，它在多种癌症类型的肿瘤模型中展现出强大且持久的抗肿瘤活性。冷冻电镜分析显示，与HB3089结合的人源STING具有与STING突变体V147L相似的结构变化，V147L是在婴儿期发病的STING相关血管病（SAVI）患者中鉴定出的一种组成型激活突变体。两种结构都突出了跨膜结构域（TMD）的构象变化，但配体结合结构域（LBD）没有先前显示的STING激活所需的180°旋转。进一步基于结构的功能分析证实了激动剂和SAVI相关突变共享的一种新的STING激活模式，其中连接LBD和TMD的连接体感知激活信号并控制LBD和TMD的构象变化以实现STING激活。总之，我们的研究结果得出了一种新的STING激活工作模型，并为针对癌症或自身免疫性疾病的STING靶向疗法的合理设计开辟了一条新途径。
