4QXP

Crystal structure of hSTING(G230I) in complex with DMXAA

4QXP の概要

• エントリーDOI: 10.2210/pdb4qxp/pdb
• 関連するPDBエントリー: 4QXO 4QXQ 4QXR
• 分子名称: Stimulator of interferon genes protein, (5,6-dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid (3 entities in total)
• 機能のキーワード: immune system, innate immunity, cgamp binding, membrane
• 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: 43763.20

構造登録者

Gao, P.,Patel, D.J. (登録日: 2014-07-21, 公開日: 2014-09-10, 最終更新日: 2024-02-28)

主引用文献

Gao, P.,Zillinger, T.,Wang, W.,Ascano, M.,Dai, P.,Hartmann, G.,Tuschl, T.,Deng, L.,Barchet, W.,Patel, D.J.
Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA.
Cell Rep, 8:1668-1676, 2014

PubMed Abstract: The drug DMXAA (5,6-dimethylxanthenone-4-acetic acid) showed therapeutic promise against solid tumors in mouse models but subsequently failed in human clinical trials. DMXAA was later discovered to activate mouse, but not human, STING, an adaptor protein in the cyclic dinucleotide cGAMP-mediated signaling pathway, inducing type I interferon expression. To facilitate the development of compounds that target human STING, we combined structural, biophysical, and cellular assays to study mouse and human chimeric proteins and their interaction with DMXAA. We identified a single substitution (G230I) that enables a DMXAA-induced conformational transition of hSTING from an inactive "open" to an active "closed" state. We also identified a substitution within the binding pocket (Q266I) that cooperates with G230I and the previously identified S162A binding-pocket point substitution, rendering hSTING highly sensitive to DMXAA. These findings should facilitate the reciprocal engineering of DMXAA analogs that bind and stimulate wild-type hSTING and their exploitation for vaccine-adjuvant and anticancer drug development.

PubMed: 25199835
DOI: 10.1016/j.celrep.2014.08.010

実験手法

X-RAY DIFFRACTION (2.51 Å)