7Q85

Crystal structure of human STING in complex with MD1193

7Q85 の概要

• エントリーDOI: 10.2210/pdb7q85/pdb
• 分子名称: Stimulator of interferon genes protein, 9-[(1R,6R,8R,13E,15R,17R,18R)-17-(6-aminopurin-9-yl)-9,18-bis(fluoranyl)-3,12-bis(oxidanyl)-3,12-bis(oxidanylidene)-2,4,7,11,16-pentaoxa-3$l^{5},12$l^{5}-diphosphatricyclo[13.3.0.0^{6,10}]octadec-13-en-8-yl]purin-6-amine (3 entities in total)
• 機能のキーワード: sting, antiviral, activator, immune system
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23847.47

構造登録者

Smola, M.,Klima, M.,Boura, E. (登録日: 2021-11-10, 公開日: 2022-10-19, 最終更新日: 2024-02-07)

主引用文献

Dejmek, M.,Brazdova, A.,Otava, T.,Polidarova, M.P.,Klima, M.,Smola, M.,Vavrina, Z.,Budesinsky, M.,Dracinsky, M.,Liboska, R.,Boura, E.,Birkus, G.,Nencka, R.
Vinylphosphonate-based cyclic dinucleotides enhance STING-mediated cancer immunotherapy.
Eur.J.Med.Chem., 259:115685-115685, 2023

PubMed Abstract: Cyclic dinucleotides (CDNs) trigger the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which plays a key role in cytosolic DNA sensing and thus in immunomodulation against infections, cell damage and cancer. However, cancer immunotherapy trials with CDNs have shown immune activation, but not complete tumor regression. Nevertheless, we designed a novel class of CDNs containing vinylphosphonate based on a STING-affinity screening assay. In vitro, acyloxymethyl phosphate/phosphonate prodrugs of these vinylphosphonate CDNs were up to 1000-fold more potent than the clinical candidate ADU-S100. In vivo, the lead prodrug induced tumor-specific T cell priming and facilitated tumor regression in the 4T1 syngeneic mouse model of breast cancer. Moreover, we solved the crystal structure of this ligand bound to the STING protein. Therefore, our findings not only validate the therapeutic potential of vinylphosphonate CDNs but also open up opportunities for drug development in cancer immunotherapy bridging innate and adaptive immunity.

PubMed: 37567057
DOI: 10.1016/j.ejmech.2023.115685

実験手法

X-RAY DIFFRACTION (2.359 Å)