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Structure of the SARS-CoV-2 Nucleocapsid: building block to viral capsid

Award Number: R21AI178427
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/05/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Structure of the SARS-CoV-2 Nucleocapsid: building block to viral capsid - SARS-CoV-2, the causative agent of an unprecedented global pandemic, has just four structural proteins. Of these, the nucleocapsid N is the most abundant protein in the virion, and plays essential roles in genome encapsidation and viral assembly. However, N has thus far defied structure determination of its full-length molecule. Indeed, there are currently no high-resolution structures of full-length N for any coronavirus, although multiple structures exist for individual domains within N. The lack of structural information on N, its assembly and its interactions and encapsidation of the genome stem from the inherent flexibility contributed by three intrinsically disordered regions. In previous work, N, in the absence of RNA or in the presence of random bacterial RNA derived from the expression system, was too flexible to allow determination of a high-resolution structure. The assembled capsid in the virion is also too heterogeneous in its flexibility, positions and conformations to afford high-resolution information. Through careful analysis using electromobility shift assays, size-exclusion and screening by electron microscopy, we have now identified portions of the SARS-CoV-2 genome that yield structurally homogeneous, purified N dimers, octamers, and 16-mers that are amenable to high-resolution structural analysis, and which represent the basic building block and likely assembly intermediates of the full capsid. We have further produced a polymerized full-length capsid in vitro that is also amenable to structural study. Here we propose cryoEM of the dimer, assembly intermediates and full length in vitro capsid, complemented by innovative native mass spectrometry and straightforward specific antibody-mediated domain identification. This work will illuminate (i) the structure and assembly of the coronavirus capsid; (ii) how the RNA genome interacts with multiple domains of the full- length N and connects along polymerized copies of N; (iii) conformational adjustments that occur in assembly, protein-protein and protein-RNA interaction sites; and (iv) sites that may be amenable targets for antiviral development.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	12/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $229,720 )
2024	2024	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	7/9/2024	NON-COMPETING CONTINUATION	$229,720
														Subtotal = $229,720

Issue Date FY: 2023 ( Subtotal = $285,857 )
2023	2023	LA JOLLA INSTITUTE FOR IMMUNOLOGY	9420 ATHENA CIR	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	7/5/2023	NEW	$285,857
														Subtotal = $285,857

Grand Total All Awards = $515,577

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Structure of the SARS-CoV-2 Nucleocapsid: building block to viral capsid

Award Number: R21AI178427

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/05/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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