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Cell Rep. 2014 Sep 25;8(6):1668-1676. doi: 10.1016/j.celrep.2014.08.010. Epub 2014 Sep 4.

Binding-pocket and lid-region substitutions render human STING sensitive to the species-specific drug DMXAA.

Author information

1
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
2
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn 53127, Germany.
3
Dermatology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
4
Laboratory of RNA Molecular Biology, Howard Hughes Medical Institute, Rockefeller University, New York, NY 10065, USA.
5
Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, University of Bonn, Bonn 53127, Germany. Electronic address: winfried.barchet@ukb.uni-bonn.de.
6
Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: pateld@mskcc.org.

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.

PMID:
25199835
PMCID:
PMC4381552
DOI:
10.1016/j.celrep.2014.08.010
[Indexed for MEDLINE]
Free PMC Article

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