7SHP

Crystal structure of hSTING in complex with c[2',3'-(ribo-2'-G, xylo-3'-A)-MP](RJ244)

7SHP の概要

• エントリーDOI: 10.2210/pdb7shp/pdb
• 分子名称: 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)
• 機能のキーワード: sting, agonist, cgamp analogs, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 87445.45

構造登録者

Xie, W.,Lama, L.,Yang, X.J.,Kuryavyi, V.,Nudelman, I.,Glickman, J.F.,Jones, R.A.,Tuschl, T.,Patel, D.J. (登録日: 2021-10-11, 公開日: 2022-10-19, 最終更新日: 2023-10-18)

主引用文献

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

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: 37536341
DOI: 10.1016/j.chembiol.2023.07.002

実験手法

X-RAY DIFFRACTION (2.2 Å)