6XNP

Crystal Structure of Human STING CTD complex with SR-717

6XNP の概要

• エントリーDOI: 10.2210/pdb6xnp/pdb
• 分子名称: Stimulator of interferon protein, 4,5-difluoro-2-{[6-(1H-imidazol-1-yl)pyridazine-3-carbonyl]amino}benzoic acid, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: agonist, complex, closed conformation, immunity, immune system
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 44137.29

構造登録者

Chin, E.N.,Yu, C.,Wolan, D.W.,Petrassi, H.M.,Lairson, L.L. (登録日: 2020-07-03, 公開日: 2020-08-26, 最終更新日: 2023-10-18)

主引用文献

Chin, E.N.,Yu, C.,Vartabedian, V.F.,Jia, Y.,Kumar, M.,Gamo, A.M.,Vernier, W.,Ali, S.H.,Kissai, M.,Lazar, D.C.,Nguyen, N.,Pereira, L.E.,Benish, B.,Woods, A.K.,Joseph, S.B.,Chu, A.,Johnson, K.A.,Sander, P.N.,Martinez-Pena, F.,Hampton, E.N.,Young, T.S.,Wolan, D.W.,Chatterjee, A.K.,Schultz, P.G.,Petrassi, H.M.,Teijaro, J.R.,Lairson, L.L.
Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic.
Science, 369:993-999, 2020

PubMed Abstract: Stimulator of interferon genes (STING) links innate immunity to biological processes ranging from antitumor immunity to microbiome homeostasis. Mechanistic understanding of the anticancer potential for STING receptor activation is currently limited by metabolic instability of the natural cyclic dinucleotide (CDN) ligands. From a pathway-targeted cell-based screen, we identified a non-nucleotide, small-molecule STING agonist, termed SR-717, that demonstrates broad interspecies and interallelic specificity. A 1.8-angstrom cocrystal structure revealed that SR-717 functions as a direct cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) mimetic that induces the same "closed" conformation of STING. SR-717 displayed antitumor activity; promoted the activation of CD8 T, natural killer, and dendritic cells in relevant tissues; and facilitated antigen cross-priming. SR-717 also induced the expression of clinically relevant targets, including programmed cell death 1 ligand 1 (PD-L1), in a STING-dependent manner.

PubMed: 32820126
DOI: 10.1126/science.abb4255

実験手法

X-RAY DIFFRACTION (1.77 Å)