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Nat Commun. 2017 Oct 9;8(1):810. doi: 10.1038/s41467-017-00864-2.

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

Author information

1
Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, 06511, USA.
2
Department of Chemistry, Howard Hughes Medical Institute, Yale University, New Haven, CT, 06511, USA.
3
SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO, 80301, USA.
4
Department of Molecular, Cellular, and Developmental Biology, Yale University, 219 Prospect Street, New Haven, CT, 06511, USA. anna.pyle@yale.edu.
5
Department of Chemistry, Howard Hughes Medical Institute, Yale University, New Haven, CT, 06511, USA. anna.pyle@yale.edu.

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.The cytokine interleukin 1α (IL-1α) plays an important role in inflammatory processes. Here the authors use SELEX to generate a modified DNA aptamer which specifically binds IL-1α, present the structure of the IL-1α/aptamer complex and show that this aptamer inhibits the IL-1α signaling pathway.

PMID:
28993621
PMCID:
PMC5634487
DOI:
10.1038/s41467-017-00864-2
[Indexed for MEDLINE]
Free PMC Article

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