Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA.

Autor: Ren X; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA., Gelinas AD; SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA., Linehan M; Department of Immunobiology, Yale University, New Haven, CT 06519, USA., Iwasaki A; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA; Department of Immunobiology, Yale University, New Haven, CT 06519, USA., Wang W; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA., Janjic N; SomaLogic, Inc., 2945 Wilderness Place, Boulder, CO 80301, USA. Electronic address: njanjic@somalogic.com., Pyle AM; Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA; Howard Hughes Medical Institute, Yale University, New Haven, CT 06520, USA. Electronic address: anna.pyle@yale.edu.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2021 Oct 15; Vol. 433 (21), pp. 167227. Date of Electronic Publication: 2021 Sep 03.
DOI: 10.1016/j.jmb.2021.167227
Abstrakt: Vertebrate organisms express a diversity of protein receptors that recognize and respond to the presence of pathogenic molecules, functioning as an early warning system for infection. As a result of mutation or dysregulated metabolism, these same innate immune receptors can be inappropriately activated, leading to inflammation and disease. One of the most important receptors for detection and response to RNA viruses is called RIG-I, and dysregulation of this protein is linked with a variety of disease states. Despite its central role in inflammatory responses, antagonists for RIG-I are underdeveloped. In this study, we use invitro selection from a pool of modified DNA aptamers to create a high affinity RIG-I antagonist. A high resolution crystal structure of the complex reveals molecular mimicry between the aptamer and the 5'-triphosphate terminus of viral ligands, which bind to the same amino acids within the CTD recognition platform of the RIG-I receptor. Our study suggests a powerful, generalizable strategy for generating immunomodulatory drugs and mechanistic tool compounds.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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