Rat and human STINGs profile similarly towards anticancer/antiviral compounds.
Rat and human STINGs profile similarly towards anticancer/antiviral compounds.
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大鼠和人类 STING 的抗癌/抗病毒化合物相似
DOI：
10.1038/srep18035
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发表时间：
2015-12-16
影响因子：
4.6
通讯作者：
Su XD
中科院分区：
文献类型：
--
作者：
Zhang H;Han MJ;Tao J;Ye ZY;Du XX;Deng MJ;Zhang XY;Li LF;Jiang ZF;Su XD
循环二核苷酸（CDN）和抗肿瘤/抗病毒剂（DMXAA和CMA）触发依赖的先天性免疫学激活。 A和CMA比人类和小鼠的刺激性，这表明大鼠更适合于刺激性药物的临床前测试。 （A140-N152）在刺激激活中的膜和胞质结构域之间，这些发现表明，大鼠的刺激在底物的偏好方面与人sting更紧密相关，这是刺激性药物的发展的基础。
Cyclic dinucleotides (CDNs) and antitumor/antiviral agents (DMXAA and CMA) trigger STING-dependent innate immunity activation. Accumulative evidences have showed that DMXAA and CMA selectively activate mouse, but not human STING signaling. The mechanism underlying this species selectivity remains poorly understood. In this report, we have shown that human and rat STINGs display more similar signaling profiles toward DMXAA and CMA than that of human and mouse STINGs, suggesting that rat is more suitable for preclinical testing of STING-targeted drugs. We have also determined the crystal structures of both apo rat STING and its complex with cyclic GMP-AMP with 2′5′ and 3′5′ phosphodiester linkage (2′3′-cGAMP), a human endogenous CDN. Structure-guided biochemical analysis also revealed the functional importance of the connecting loop (A140-N152) between membrane and cytosolic domains in STING activation. Taken together, these findings reveal that rat STING is more closely related to human STING in terms of substrate preference, serving as a foundation for the development of STING-targeted drugs.