PDBsum entry 6a06

Signaling protein

PDB id: 6a06

Contents

Protein chains

188 a.a.

Ligands

SO4 ×4

1SY

Waters ×233

References listed in PDB file

Key reference

• Title: Crystal structures of porcine sting^cbd-Cdn complexes reveal the mechanism of ligand recognition and discrimination of sting proteins.
• Authors: X.Cong, Z.Yuan, Y.Du, B.Wu, D.Lu, X.Wu, Y.Zhang, F.Li, B.Wei, J.Li, J.Wu, S.Xu, J.Wang, J.Qi, G.Shang, L.Gu.
• Ref.: J Biol Chem, 2019, 294, 11420-11432. [DOI no: 10.1074/jbc.RA119.007367]
• PubMed id: 31167783

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 (STING^CBD) in complex with CDNs at 1.76-2.6 Å resolution revealed that porcine STING^CBD, 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.