4LOI

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

4LOI の概要

• エントリーDOI: 10.2210/pdb4loi/pdb
• 関連するPDBエントリー: 4LOH 4LOJ 4LOK 4LOL
• 分子名称: Stimulator of interferon genes protein, PHOSPHATE ION, 2-amino-9-[(1R,3R,6R,8R,9R,11S,14R,16R,17R,18R)-16-(6-amino-9H-purin-9-yl)-3,11,17,18-tetrahydroxy-3,11-dioxido-2,4,7,10,12,15-hexaoxa-3,11-diphosphatricyclo[12.2.1.1~6,9~]octadec-8-yl]-1,9-dihydro-6H-purin-6-one, ... (4 entities in total)
• 機能のキーワード: innate immunity, immune system
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Endoplasmic reticulum membrane; Multi-pass membrane protein: Q86WV6
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 43817.70

構造登録者

Gao, P.,Patel, D.J. (登録日: 2013-07-12, 公開日: 2013-08-14, 最終更新日: 2024-02-28)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.89 Å)