Crystal structures of porcine STING CBD -CDN complexes reveal the mechanism of ligand recognition and discrimination of STING proteins

• Published in: The Journal of biological chemistry Vol. 294; no. 30; p. 11420
• Main Authors: Cong, Xiaoyan, Yuan, Zenglin, Du, Yijun, Wu, Bo, Lu, Defen, Wu, Xiangju, Zhang, Youjia, Li, Feng, Wei, Bin, Li, Jun, Wu, Jiaqiang, Xu, Sujuan, Wang, Jinbao, Qi, Jing, Shang, Guijun, Gu, Lichuan
• Format: Journal Article
• Language: English
• Published: United States 26.07.2019
• Subjects: Animals; Binding Sites; Crystallography, X-Ray; Dinucleoside Phosphates - chemistry; Dinucleoside Phosphates - metabolism; Ligands; Membrane Proteins - chemistry; Membrane Proteins - metabolism; Molecular Structure; Nucleotides, Cyclic - chemistry; Nucleotides, Cyclic - metabolism; Protein Binding; Swine; signaling; cyclic diadenosine monophosphate (c-di-AMP); interferon; pattern recognition receptor (PRR); pathogen-associated molecular pattern (PAMP)
• ISSN: 1083-351X

The cyclic dinucleotide (CDN)- imulator of terferon enes (STING) pathway plays an important role in the detection of viral and bacterial pathogens in animals. Previous studies have shown that the metazoan second messenger cyclic [G(2',5')pA(3',5')p] (2',3'-cGAMP) generated by cyclic GMP-AMP synthase cGAS binds STING with high affinity compared with bacterial CDNs such as c-di-GMP, c-di-AMP, and 3',3'-cGAMP. Despite recent progress indicating that the CDN-binding domain (CBD) of dimeric STING binds asymmetric 2',3'-cGAMP preferentially over symmetric 3',3'-CDNs, it remains an open question whether STING molecules, such as human STING, adopt a symmetric dimeric conformation to efficiently engage its asymmetric ligand. Here, structural studies of the CBD from porcine STING (STING ) in complex with CDNs at 1.76-2.6 Å resolution revealed that porcine STING , unlike its human and mouse counterparts, can adopt an asymmetric ligand-binding pocket to accommodate the CDNs. We observed that the extensive interactions and shape complementarity between asymmetric 2',3'-cGAMP and the ligand-binding pocket make it the most preferred ligand for porcine STING and that geometry constraints limit the binding between symmetric 3',3'-CDN and porcine STING. The ligand-discrimination mechanism of porcine STING observed here expands our understanding of how the CDN-STING pathway is activated and of its role in antiviral defense.