TY - JOUR
T1 - Crystal structures of porcine STINGCBD–CDN complexes reveal the mechanism of ligand recognition and discrimination of STING proteins
AU - Cong, Xiaoyan
AU - Yuan, Zenglin
AU - Du, Yijun
AU - Wu, Bo
AU - Lu, Defen
AU - Wu, Xiangju
AU - Zhang, Youjia
AU - Li, Feng
AU - Wei, Bin
AU - Li, Jun
AU - Wu, Jiaqiang
AU - Xu, Sujuan
AU - Wang, Jinbao
AU - Qi, Jing
AU - Shang, Guijun
AU - Gu, Lichuan
N1 - Publisher Copyright:
© 2019 Cong et al.
PY - 2019/7/26
Y1 - 2019/7/26
N2 - The cyclic dinucleotide (CDN)-stimulator of interferon genes (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 (STINGCBD) in complex with CDNs at 1.76 –2.6 Å resolution revealed that porcine STINGCBD, 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.
AB - The cyclic dinucleotide (CDN)-stimulator of interferon genes (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 (STINGCBD) in complex with CDNs at 1.76 –2.6 Å resolution revealed that porcine STINGCBD, 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.
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U2 - 10.1074/jbc.RA119.007367
DO - 10.1074/jbc.RA119.007367
M3 - Article
C2 - 31167783
AN - SCOPUS:85070073721
SN - 0021-9258
VL - 294
SP - 11420
EP - 11432
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 30
ER -