6XNN

Crystal Structure of Mouse STING CTD complex with SR-717.

Summary for 6XNN

• Entry DOI: 10.2210/pdb6xnn/pdb
• Descriptor: Stimulator of interferon genes protein, 4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}benzoic acid (3 entities in total)
• Functional Keywords: agonist, complex, closed conformation, immunity, immune system
• Biological source: Mus musculus (Mouse)
• Total number of polymer chains: 2
• Total formula weight: 43607.28

Authors

Chin, E.N.,Yu, C.,Wolan, D.W.,Petrassi, H.M.,Lairson, L.L. (deposition date: 2020-07-03, release date: 2020-08-26, Last modification date: 2023-10-18)

Primary citation

Chin, E.N.,Yu, C.,Vartabedian, V.F.,Jia, Y.,Kumar, M.,Gamo, A.M.,Vernier, W.,Ali, S.H.,Kissai, M.,Lazar, D.C.,Nguyen, N.,Pereira, L.E.,Benish, B.,Woods, A.K.,Joseph, S.B.,Chu, A.,Johnson, K.A.,Sander, P.N.,Martinez-Pena, F.,Hampton, E.N.,Young, T.S.,Wolan, D.W.,Chatterjee, A.K.,Schultz, P.G.,Petrassi, H.M.,Teijaro, J.R.,Lairson, L.L.
Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic.
Science, 369:993-999, 2020

PubMed Abstract: Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8 T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.

PubMed: 32820126
DOI: 10.1126/science.abb4255

Experimental method

X-RAY DIFFRACTION (2.49 Å)