7SHP
Crystal structure of hSTING in complex with c[2',3'-(ribo-2'-G, xylo-3'-A)-MP](RJ244)
Summary for 7SHP
| Entry DOI | 10.2210/pdb7shp/pdb |
| Descriptor | Stimulator of interferon genes protein, (2S,5R,7R,8R,10S,12aR,14R,15R,15aR,16R)-7-(2-amino-6-oxo-3,6-dihydro-9H-purin-9-yl)-14-(6-amino-9H-purin-9-yl)-2,10,15,16-tetrahydroxyoctahydro-2H,10H,12H-5,8-methano-2lambda~5~,10lambda~5~-furo[3,2-l][1,3,6,9,11,2,10]pentaoxadiphosphacyclotetradecine-2,10-dione (3 entities in total) |
| Functional Keywords | sting, agonist, cgamp analogs, immune system |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 4 |
| Total formula weight | 87445.45 |
| Authors | Xie, W.,Lama, L.,Yang, X.J.,Kuryavyi, V.,Nudelman, I.,Glickman, J.F.,Jones, R.A.,Tuschl, T.,Patel, D.J. (deposition date: 2021-10-11, release date: 2022-10-19, Last modification date: 2023-10-18) |
| Primary citation | Xie, W.,Lama, L.,Yang, X.,Kuryavyi, V.,Bhattacharya, S.,Nudelman, I.,Yang, G.,Ouerfelli, O.,Glickman, J.F.,Jones, R.A.,Tuschl, T.,Patel, D.J. Arabinose- and xylose-modified analogs of 2',3'-cGAMP act as STING agonists. Cell Chem Biol, 2023 Cited by PubMed Abstract: Stimulator of interferon genes (STING) agonists are promising candidates for vaccine adjuvants and antitumor immune stimulants. The most potent natural agonist of STING, 2',3'-cyclic GMP-AMP (2',3'-cGAMP), is subject to nuclease-mediated inherent metabolic instability, thereby placing limits on its clinical efficacy. Here, we report on a new class of chemically synthesized sugar-modified analogs of 2',3'-cGAMP containing arabinose and xylose sugar derivatives that bind mouse and human STING alleles with high affinity. The co-crystal structures demonstrate that such analogs act as 2',3'-cGAMP mimetics that induce the "closed" conformation of human STING. These analogs show significant resistance to hydrolysis mediated by ENPP1 and increased stability in human serum, while retaining similar potency as 2',3'-cGAMP at inducing IFN-β secretion from human THP1 cells. The arabinose- and xylose-modified 2',3'-cGAMP analogs open a new strategy for overcoming the inherent nuclease-mediated vulnerability of natural ribose cyclic nucleotides, with the additional benefit of high translational potential as cancer therapeutics and vaccine adjuvants. PubMed: 37536341DOI: 10.1016/j.chembiol.2023.07.002 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.2 Å) |
Structure validation
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