9SWR

Stimulator of interferon genes protein mutant - W119K M120K

Summary for 9SWR

• Entry DOI: 10.2210/pdb9swr/pdb
• Related: 9SWM
• EMDB information: 55325
• Descriptor: Stimulator of interferon genes protein (1 entity in total)
• Functional Keywords: sting, innate immunity, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 253064.58

Authors

Xu, P.,Zhang, B.,Meng, Y.,Ablasser, A. (deposition date: 2025-10-07, release date: 2026-05-27, Last modification date: 2026-07-08)

Primary citation

Zhang, B.,Xu, P.,Meng, Y.,Gallay, L.,Lestelle, F.,Morel, H.,Fremond, M.L.,Correia, B.E.,Ablasser, A.
The mutational landscape of STING-induced immunity.
Nature, 2026

PubMed Abstract: Stimulator of interferon genes (STING) is an evolutionary conserved immune signalling protein with key roles in host defence, cancer, senescence and inflammation. Downstream of STING, type I interferon, inflammatory cytokine signalling and non-canonical autophagy are governed by a multilayered mechanism integrating ligand-induced structural transitions, protein-protein interactions and coordinated intracellular trafficking. Despite its central role in immunity and relevance as therapeutic target, the sequence elements that govern STING (in)activation in cells remain incompletely understood. Here we developed a massively parallel assay to systematically chart the sequence-function landscape of STING. Profiling thousands of single amino-acid variants, we identified structural and functional determinants that shape the immunostimulatory capacity of STING and its ability to translate ligand recognition into distinct signalling outputs. Cryogenic-electron microscopy structures of select STING hyperactive variants revealed new regulatory principles dictating conformational transition from inactive to signalling-competent states of STING. Mutational effects are widespread across the functional landscape and can sensitize STING towards the natural ligand 2'3'-cGAMP or decouple interferon induction from non-canonical autophagy, demonstrating a diversity of possible responses that can be accessed through single point substitutions. Finally, our data showed the clinical and evolutionary relevance of naturally occurring STING protein variants. Collectively, these findings define molecular principles that tune STING activity and chart the landscape of its functional potential across immune contexts.

PubMed: 42343134
DOI: 10.1038/s41586-026-10685-3

Experimental method

ELECTRON MICROSCOPY (2.86 Å)