Crystal structures of porcine STINGCBD–CDN complexes reveal the mechanism of ligand recognition and discrimination of STING proteins

Xiaoyan Cong, Zenglin Yuan, Yijun Du, Bo Wu, Defen Lu, Xiangju Wu, Youjia Zhang, Feng Li, Bin Wei, Jun Li, Jiaqiang Wu, Sujuan Xu, Jinbao Wang, Jing Qi, Guijun Shang, Lichuan Gu

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)11420-11432
Number of pages13
JournalJournal of Biological Chemistry
Volume294
Issue number30
DOIs
StatePublished - Jul 26 2019

Bibliographical note

Publisher Copyright:
© 2019 Cong et al.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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