4QXP

Crystal structure of hSTING(G230I) in complex with DMXAA

Summary for 4QXP

• Entry DOI: 10.2210/pdb4qxp/pdb
• Related: 4QXO 4QXQ 4QXR
• Descriptor: Stimulator of interferon genes protein, (5,6-dimethyl-9-oxo-9H-xanthen-4-yl)acetic acid (3 entities in total)
• Functional Keywords: immune system, innate immunity, cgamp binding, membrane
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Multi-pass membrane protein: Q86WV6
• Total number of polymer chains: 2
• Total formula weight: 43763.20

Authors

Gao, P.,Patel, D.J. (deposition date: 2014-07-21, release date: 2014-09-10, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.51 Å)