6CY7

Human Stimulator of Interferon Genes

Summary for 6CY7

• Entry DOI: 10.2210/pdb6cy7/pdb
• Descriptor: Stimulator of interferon genes protein, (2R,3R,3aS,5R,7aR,9R,10R,10aS,12R,14aR)-2,9-bis(6-amino-9H-purin-9-yl)octahydro-2H,7H-difuro[3,2-d:3',2'-j][1,3,7,9,2,8 ]tetraoxadiphosphacyclododecine-3,5,10,12-tetrol 5,12-dioxide, IMIDAZOLE, ... (5 entities in total)
• Functional Keywords: human sting, complex, cyclic-di-amp, tmem173, ala230 allelle, 230a/232r, immune system
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 27957.21

Authors

Fernandez, D.,Li, L.,Ergun, S.L. (deposition date: 2018-04-04, release date: 2019-03-13, Last modification date: 2023-10-04)

Primary citation

Ergun, S.L.,Fernandez, D.,Weiss, T.M.,Li, L.
STING Polymer Structure Reveals Mechanisms for Activation, Hyperactivation, and Inhibition.
Cell, 178:290-301.e10, 2019

PubMed Abstract: How the central innate immune protein, STING, is activated by its ligands remains unknown. Here, using structural biology and biochemistry, we report that the metazoan second messenger 2'3'-cGAMP induces closing of the human STING homodimer and release of the STING C-terminal tail, which exposes a polymerization interface on the STING dimer and leads to the formation of disulfide-linked polymers via cysteine residue 148. Disease-causing hyperactive STING mutations either flank C148 and depend on disulfide formation or reside in the C-terminal tail binding site and cause constitutive C-terminal tail release and polymerization. Finally, bacterial cyclic-di-GMP induces an alternative active STING conformation, activates STING in a cooperative manner, and acts as a partial antagonist of 2'3'-cGAMP signaling. Our insights explain the tight control of STING signaling given varying background activation signals and provide a therapeutic hypothesis for autoimmune syndrome treatment.

PubMed: 31230712
DOI: 10.1016/j.cell.2019.05.036

Experimental method

X-RAY DIFFRACTION (2.2 Å)