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Title: Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling

Abstract

IL-1α is an essential cytokine that contributes to inflammatory responses and is implicated in various forms of pathogenesis and cancer. Here we report a naphthyl modified DNA aptamer that specifically binds IL-1α and inhibits its signaling pathway. By solving the crystal structure of the IL-1α/aptamer, we provide a high-resolution structure of this critical cytokine and we reveal its functional interaction interface with high-affinity ligands. The non-helical aptamer, which represents a highly compact nucleic acid structure, contains a wealth of new conformational features, including an unknown form of G-quadruplex. The IL-1α/aptamer interface is composed of unusual polar and hydrophobic elements, along with an elaborate hydrogen bonding network that is mediated by sodium ion. IL-1α uses the same interface to interact with both the aptamer and its cognate receptor IL-1RI, thereby suggesting a novel route to immunomodulatory therapeutics.

Authors:
; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIHHHMI
OSTI Identifier:
1400301
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 8; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY

Citation Formats

Ren, Xiaoming, Gelinas, Amy D., von Carlowitz, Ira, Janjic, Nebojsa, and Pyle, Anna Marie. Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling. United States: N. p., 2017. Web. doi:10.1038/s41467-017-00864-2.
Ren, Xiaoming, Gelinas, Amy D., von Carlowitz, Ira, Janjic, Nebojsa, & Pyle, Anna Marie. Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling. United States. doi:10.1038/s41467-017-00864-2.
Ren, Xiaoming, Gelinas, Amy D., von Carlowitz, Ira, Janjic, Nebojsa, and Pyle, Anna Marie. Mon . "Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling". United States. doi:10.1038/s41467-017-00864-2.
@article{osti_1400301,
title = {Structural basis for IL-1α recognition by a modified DNA aptamer that specifically inhibits IL-1α signaling},
author = {Ren, Xiaoming and Gelinas, Amy D. and von Carlowitz, Ira and Janjic, Nebojsa and Pyle, Anna Marie},
abstractNote = {IL-1α is an essential cytokine that contributes to inflammatory responses and is implicated in various forms of pathogenesis and cancer. Here we report a naphthyl modified DNA aptamer that specifically binds IL-1α and inhibits its signaling pathway. By solving the crystal structure of the IL-1α/aptamer, we provide a high-resolution structure of this critical cytokine and we reveal its functional interaction interface with high-affinity ligands. The non-helical aptamer, which represents a highly compact nucleic acid structure, contains a wealth of new conformational features, including an unknown form of G-quadruplex. The IL-1α/aptamer interface is composed of unusual polar and hydrophobic elements, along with an elaborate hydrogen bonding network that is mediated by sodium ion. IL-1α uses the same interface to interact with both the aptamer and its cognate receptor IL-1RI, thereby suggesting a novel route to immunomodulatory therapeutics.},
doi = {10.1038/s41467-017-00864-2},
journal = {Nature Communications},
number = 1,
volume = 8,
place = {United States},
year = {Mon Oct 09 00:00:00 EDT 2017},
month = {Mon Oct 09 00:00:00 EDT 2017}
}