9CT3

HsSTING with SR-717 and C53

Summary for 9CT3

• Entry DOI: 10.2210/pdb9ct3/pdb
• EMDB information: 45897
• Descriptor: Stimulator of interferon genes protein, 4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}benzoic acid, 1-[(2-chloro-6-fluorophenyl)methyl]-3,3-dimethyl-2-oxo-N-[(2,4,6-trifluorophenyl)methyl]-2,3-dihydro-1H-indole-6-carboxamide (3 entities in total)
• Functional Keywords: innate immunity, membrane protein, immune system
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 163346.79

Authors

Gharpure, A.,Sulpizio, A.,Lairson, L.L.,Ward, A.B. (deposition date: 2024-07-24, release date: 2025-04-23)

Primary citation

Gharpure, A.,Sulpizio, A.,Loeffler, J.R.,Fernandez-Quintero, M.L.,Tran, A.S.,Lairson, L.L.,Ward, A.B.
Distinct oligomeric assemblies of STING induced by non-nucleotide agonists.
Nat Commun, 16:3440-3440, 2025

PubMed Abstract: STING plays essential roles coordinating innate immune responses to processes that range from pathogenic infection to genomic instability. Its adaptor function is activated by cyclic dinucleotide (CDN) secondary messengers originating from self (2'3'-cGAMP) or bacterial sources (3'3'-CDNs). Different classes of CDNs possess distinct binding modes, stabilizing STING's ligand-binding domain (LBD) in either a closed or open conformation. The closed conformation, induced by the endogenous ligand 2'3'-cGAMP, has been extensively studied using cryo-EM. However, significant questions remain regarding the structural basis of STING activation by open conformation-inducing ligands. Using cryo-EM, we investigate potential differences in conformational changes and oligomeric assemblies of STING for closed and open conformation-inducing synthetic agonists. While we observe a characteristic 180° rotation for both classes, the open-LBD inducing agonist diABZI-3 uniquely induces a quaternary structure reminiscent but distinct from the reported autoinhibited state of apo-STING. Additionally, we observe slower rates of activation for this ligand class in functional assays, which collectively suggests the existence of a potential additional regulatory mechanism for open conformation-inducing ligands that involves head-to-head interactions and restriction of curved oligomer formation. These observations have potential implications in the selection of an optimal class of STING agonist in the context of a defined therapeutic application.

PubMed: 40216780
DOI: 10.1038/s41467-025-58641-5

Experimental method

ELECTRON MICROSCOPY (3.09 Å)