4LOH

Crystal structure of hSTING(H232) in complex with c[G(2',5')pA(3',5')p]

Summary for 4LOH

• Entry DOI: 10.2210/pdb4loh/pdb
• Related: 4LOI 4LOJ 4LOK 4LOL
• Descriptor: Stimulator of interferon genes protein, cGAMP (3 entities in total)
• Functional Keywords: innate immunity, immune system
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Multi-pass membrane protein: Q86WV6
• Total number of polymer chains: 2
• Total formula weight: 43722.73

Authors

Gao, P.,Patel, D.J. (deposition date: 2013-07-12, release date: 2013-08-14, Last modification date: 2024-02-28)

Primary citation

Gao, P.,Ascano, M.,Zillinger, T.,Wang, W.,Dai, P.,Serganov, A.A.,Gaffney, B.L.,Shuman, S.,Jones, R.A.,Deng, L.,Hartmann, G.,Barchet, W.,Tuschl, T.,Patel, D.J.
Structure-Function Analysis of STING Activation by c[G(2',5')pA(3',5')p] and Targeting by Antiviral DMXAA.
Cell(Cambridge,Mass.), 154:748-762, 2013

PubMed Abstract: Binding of dsDNA by cyclic GMP-AMP (cGAMP) synthase (cGAS) triggers formation of the metazoan second messenger c[G(2',5')pA(3',5')p], which binds the signaling protein STING with subsequent activation of the interferon (IFN) pathway. We show that human hSTING(H232) adopts a "closed" conformation upon binding c[G(2',5')pA(3',5')p] and its linkage isomer c[G(2',5')pA(2',5')p], as does mouse mSting(R231) on binding c[G(2',5')pA(3',5')p], c[G(3',5')pA(3',5')p] and the antiviral agent DMXAA, leading to similar "closed" conformations. Comparing hSTING to mSting, 2',5'-linkage-containing cGAMP isomers were more specific triggers of the IFN pathway compared to the all-3',5'-linkage isomer. Guided by structural information, we identified a unique point mutation (S162A) placed within the cyclic-dinucleotide-binding site of hSTING that rendered it sensitive to the otherwise mouse-specific drug DMXAA, a conclusion validated by binding studies. Our structural and functional analysis highlights the unexpected versatility of STING in the recognition of natural and synthetic ligands within a small-molecule pocket created by the dimerization of STING.

PubMed: 23910378
DOI: 10.1016/j.cell.2013.07.023

Experimental method

X-RAY DIFFRACTION (2.25 Å)