Structural stabilization of the intrinsically disordered SARS-CoV-2 N by binding to RNA sequences engineered from the viral genome fragment

Sara Landeras-Bueno (), Chitra Hariharan, Ruben Diaz Avalos, Andrew S. Norris, Dalton T. Snyder, Kathryn M. Hastie, Stephanie Harkins, Michelle Zandonatti, Roshan R. Rajamanickam, Eduardo Olmedillas, Robyn Miller, Sujan Shresta, Vicki H. Wysocki and Erica Ollmann Saphire ()
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Sara Landeras-Bueno: La Jolla Institute for Immunology
Chitra Hariharan: La Jolla Institute for Immunology
Ruben Diaz Avalos: La Jolla Institute for Immunology
Andrew S. Norris: The Ohio State University
Dalton T. Snyder: The Ohio State University
Kathryn M. Hastie: La Jolla Institute for Immunology
Stephanie Harkins: La Jolla Institute for Immunology
Michelle Zandonatti: La Jolla Institute for Immunology
Roshan R. Rajamanickam: La Jolla Institute for Immunology
Eduardo Olmedillas: La Jolla Institute for Immunology
Robyn Miller: La Jolla Institute for Immunology
Sujan Shresta: La Jolla Institute for Immunology
Vicki H. Wysocki: The Ohio State University
Erica Ollmann Saphire: La Jolla Institute for Immunology

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The nucleocapsid N is one of four structural proteins of the coronaviruses. Its essential role in genome encapsidation makes it a critical therapeutic target for COVID-19 and related diseases. However, the inherent disorder of full-length N hampers its structural analysis. Here, we describe a stepwise method using viral-derived RNAs to stabilize SARS-CoV-2 N for EM analysis. We identify pieces of RNA from the SARS-CoV-2 genome that promote the formation of structurally homogeneous N dimers, intermediates of assembly, and filamentous capsid-like structures. Building on these results, we engineer a symmetric RNA to stabilize N protein dimers, the building block of high-order assemblies, for EM studies. We combine domain-specific monoclonal antibodies against N with chemical cross-linking mass spectrometry to validate the spatial arrangement of the N domains within the dimer. Additionally, our cryo-EM analysis reveals novel antigenic sites on the N protein. Our findings provide insights into N protein´s architectural and antigenic principles, which can guide design of pan-coronavirus therapeutics.

Date: 2025
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DOI: 10.1038/s41467-025-61861-4

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