Evolving A RIG-I Antagonist: A Modified DNA Aptamer Mimics Viral RNA. Issue 21 (15th October 2021)

• Record Type: Journal Article
• Authors: Ren, Xiaoming; Gelinas, Amy D.; Linehan, Melissa; Iwasaki, Akiko; Wang, Wenshuai; Janjic, Nebojsa; Pyle, Anna Marie
• Is Part Of: Journal of molecular biology. Volume 433:Issue 21(2021)
• Publication Date: 2021-10-15
• Subjects: innate immunity -- molecular recognition -- DNA structure -- nucleic acid folding -- in-vitro; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.167227
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Despite its central role in antiviral immunity antagonists for RIG-I are underdeveloped. We selected modified DNA aptamers with high affinity binding to the RIG-I CTD. A crystal structure of the complex reveals aptamer mimicry of viral RNA with a different fold. The DNA base modifications fold into a hydrophobic core leading to a round aptamer. The work suggests a strategy for generating immunomodulatory drugs and tool compounds. Abstract: 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.