5grm | pdb_00005grm
Crystal structure of rat STING in complex with cyclic GMP-AMP with 2'5'and 3'5'phosphodiester linkage(2'3'-cGAMP)
Structural highlights
Function[STING_RAT] Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced in response to DNA virus in the cytosol: upon binding of c-di-GMP or cGAMP, autoinhibition is alleviated and TMEM173/STING is able to activate both NF-kappa-B and IRF3 transcription pathways to induce expression of type I interferon and exert a potent anti-viral state (PubMed:26669264). May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). Mediates death signaling via activation of the extracellular signal-regulated kinase (ERK) pathway (By similarity). Exhibits 2',3' phosphodiester linkage-specific ligand recognition. Can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP; the precise binding affinity may be species-specific and rat TMEM173/STING is preferentially activated by 3'-3' linked cGAMP (PubMed:26669264).[UniProtKB:Q86WV6][1] Publication Abstract from PubMedCyclic 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. Rat and human STINGs profile similarly towards anticancer/antiviral compounds.,Zhang H, Han MJ, Tao J, Ye ZY, Du XX, Deng MJ, Zhang XY, Li LF, Jiang ZF, Su XD Sci Rep. 2015 Dec 16;5:18035. doi: 10.1038/srep18035. PMID:26669264[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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