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Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA

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 sig...

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Autores principales: Gao, Pu, Zillinger, Thomas, Wang, Weiyi, Ascano, Manuel, Dai, Peihong, Hartmann, Gunther, Tuschl, Thomas, Deng, Liang, Barchet, Winfried, Patel, Dinshaw J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381552/
https://www.ncbi.nlm.nih.gov/pubmed/25199835
http://dx.doi.org/10.1016/j.celrep.2014.08.010
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author Gao, Pu
Zillinger, Thomas
Wang, Weiyi
Ascano, Manuel
Dai, Peihong
Hartmann, Gunther
Tuschl, Thomas
Deng, Liang
Barchet, Winfried
Patel, Dinshaw J.
author_facet Gao, Pu
Zillinger, Thomas
Wang, Weiyi
Ascano, Manuel
Dai, Peihong
Hartmann, Gunther
Tuschl, Thomas
Deng, Liang
Barchet, Winfried
Patel, Dinshaw J.
author_sort Gao, Pu
collection PubMed
description 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 anti-cancer drug development.
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spelling pubmed-43815522015-04-01 Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA Gao, Pu Zillinger, Thomas Wang, Weiyi Ascano, Manuel Dai, Peihong Hartmann, Gunther Tuschl, Thomas Deng, Liang Barchet, Winfried Patel, Dinshaw J. Cell Rep Article 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 anti-cancer drug development. 2014-09-04 2014-09-25 /pmc/articles/PMC4381552/ /pubmed/25199835 http://dx.doi.org/10.1016/j.celrep.2014.08.010 Text en This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).
spellingShingle Article
Gao, Pu
Zillinger, Thomas
Wang, Weiyi
Ascano, Manuel
Dai, Peihong
Hartmann, Gunther
Tuschl, Thomas
Deng, Liang
Barchet, Winfried
Patel, Dinshaw J.
Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA
title Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA
title_full Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA
title_fullStr Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA
title_full_unstemmed Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA
title_short Binding-Pocket and Lid-Region Substitutions Render Human STING Sensitive to the Species-Specific Drug DMXAA
title_sort binding-pocket and lid-region substitutions render human sting sensitive to the species-specific drug dmxaa
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4381552/
https://www.ncbi.nlm.nih.gov/pubmed/25199835
http://dx.doi.org/10.1016/j.celrep.2014.08.010
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