title: Rat and human STINGs profile similarly towards anticancer/antiviral compounds.
abstract: 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.
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Min-Jie
authors.initials: MJ
authors.lastname: Han
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Zhao-Yang
authors.initials: ZY
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Du
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Ming-Jing
authors.initials: MJ
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Lan-Fen
authors.initials: LF
authors.lastname: Li
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Zheng-Fan
authors.initials: ZF
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Protein and Plant Gene Research, and Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Su
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009712:Nucleotides, Cyclic / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology; D000099197:STING Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D008565:Membrane Proteins; D009712:Nucleotides, Cyclic; D044004:Xanthones; C532857:STING1 protein, human; D000099197:STING Protein; C574737:Sting1 protein, rat; C584311:cyclic guanosine monophosphate-adenosine monophosphate; C066668:vadimezan