9CUD

Human STING G230A/R293Q variant bound to diABZI-i

This is a non-PDB format compatible entry.

Summary for 9CUD

• Entry DOI: 10.2210/pdb9cud/pdb
• Descriptor: Stimulator of interferon genes protein, (2E)-1-[(2E)-4-{(2E)-5-carbamoyl-2-[(1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino]-3-methyl-2,3-dihydro-1H-1,3-benzimidazol-1-yl}-2,3-dimethylbut-2-en-1-yl]-2-[(1-ethyl-3-methyl-1H-pyrazole-5-carbonyl)imino]-7-[(3-methoxyphenyl)methoxy]-3-methyl-2,3-dihydro-1H-1,3-benzimidazole-5-carboxamide (3 entities in total)
• Functional Keywords: innate immunity, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 48946.79

Authors

Critton, D.A. (deposition date: 2024-07-26, release date: 2025-06-18, Last modification date: 2025-07-16)

Primary citation

Xie, T.,Ruzanov, M.,Critton, D.,Merselis, L.,Naglich, J.,Sack, J.S.,Zhang, P.,Xie, C.,Tredup, J.,Stine, L.B.,Messier, C.,Hope, D.L.,Caceres-Cortes, J.,Mueller, L.,Dyckman, A.J.,Newitt, J.A.,Choudhury, A.,Wilson, S.C.
Orthosteric STING inhibition elucidates molecular correction of SAVI STING.
Nat Commun, 16:5695-5695, 2025

PubMed Abstract: While the progression of STING activators into the clinic has been successful, the discovery and clinical progression of STING inhibitors remain elusive. Questions persist about the molecular properties needed to distinguish between a STING activator and inhibitor, particularly within SAVI disease, a monogenic autoinflammatory disease that renders STING constitutively active, and how different conformations correlate to function. In this work, we use an orthosteric STING activator and inhibitor from the same chemical series to discover that STING M271 is a critical residue for molecular activation that can be leveraged as a unique molecular signature for pharmacological or genetically driven activation and inhibition. Furthermore, we demonstrate how the therapeutic requirements of a molecular corrector of SAVI STING differs from an orthosteric STING inhibitor, and why this is important for the SAVI disease population.

PubMed: 40595544
DOI: 10.1038/s41467-025-60632-5

Experimental method

X-RAY DIFFRACTION (1.53 Å)