A COVID-19 antibody curbs SARS-CoV-2 nucleocapsid protein-induced complement hyperactivation

Kang, Shiyang; Yang, Mei; He, Songtao; Wang, Yueming; Chen, Xiaoxue; Chen, Yao-Qing; Hong, Zhongsi; Liu, Jing; Jiang, Guanmin; Chen, Qiuyue; Zhou, Ziliang; Zhou, Zhechong; Huang, Zhenguo; Huang, Xi; He, Huanhuan; Zheng, Wenwei; Liao, Hua‐Xin; Xiao, Fei; Shan, Hong; Chen, Shoudeng

doi:10.21203/rs.3.rs-106760/v1

Cited by 3 publications

(3 citation statements)

References 42 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Epitopes in the dimerization domain Five of the antibodies tested in this study bound to the Nucleocapsid's dimerization domain (N-DD, amino acids 257 to 364, Figure 4). The N-DD forms a symmetrical dimer in which two betastrands from each monomer form a central four-stranded antiparallel beta-sheet with domainswapped interactions (Yang et al, 2020). This core structure is surrounded in the back and on the sides by alpha-helices of varying lengths.…”

Section: Validation Of Deep Mutational Scanning Experimentsmentioning

confidence: 99%

Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests

Frank

Keen

Rao

et al. 2022

Preprint

View full text Add to dashboard Cite

Widespread and frequent testing is critical to prevent the spread of COVID-19, and rapid antigen tests are the diagnostic tool of choice in many settings. With new viral variants continuously emerging and spreading rapidly, the effect of mutations on antigen test performance is a major concern. In response to the spread of variants the National Institutes of Health’s Rapid Acceleration of Diagnostics (RADx®) initiative created a Variant Task Force to assess the impact of emerging SARS-CoV-2 variants on in vitro diagnostic testing. To evaluate the impact of mutations on rapid antigen tests we developed a lentivirus-mediated mammalian surface-display platform for the SARS-CoV-2 Nucleocapsid protein, the target of the majority of rapid antigen tests. We employed deep mutational scanning (DMS) to directly measure the effect of all possible Nucleocapsid point mutations on antibody binding by 17 diagnostic antibodies used in 11 commercially available antigen tests with FDA emergency use authorization (EUA). The results provide a complete map of the antibodies’ epitopes and their susceptibility to mutational escape. This approach identifies linear epitopes, conformational epitopes, as well as allosteric escape mutations in any region of the Nucleocapsid protein. All 17 antibodies tested exhibit distinct escape mutation profiles, even among antibodies recognizing the same folded domain. Our data predict no vulnerabilities of rapid antigen tests for detection of mutations found in currently and previously dominant variants of concern and interest. We confirm this using the commercial tests and sequence-confirmed COVID-19 patient samples. The antibody escape mutation profiles generated here serve as a valuable resource for predicting the performance of rapid antigen tests against past, current, as well as any possible future variants of SARS-CoV-2, establishing the direct clinical and public health utility of our system. Further, our mammalian surface-display platform combined with DMS is a generalizable platform for complete mapping of protein-protein interactions.

show abstract

Section: Validation Of Deep Mutational Scanning Experimentsmentioning

confidence: 99%

Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests

Frank

Keen

Rao

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…NTD is a major RNA-binding domain, and its complex structure with single-and double-stranded RNA has been determined by solution NMR 56 . CTD is the dimerization domain, and its dimeric structure has been obtained by X-ray crystallography 57,58 , suggesting that it also has an RNA-binding ability. The calculation results of these structures are registered in FMODB, and representative analysis of the complex structure of NTD and single-stranded RNA (PDBID:7ACT, FMODB ID: N3Y7Q) is described below.…”

Section: Nucleocapsid (N) Proteinmentioning

confidence: 99%

Special feature of COVID-19 in FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2 related proteins

Fukuzawa

Kato

Watanabe

et al. 2021

Preprint

View full text Add to dashboard Cite

SARS-CoV-2 is the causative agent of coronavirus(known as , the virus causing the current pandemic. there are ongoing researches to develop effective therapeutics and vaccines against COVID-19 using various methods, and many results have been published.The structure-based drug design of SARS-CoV-2 related proteins is promising. However, 2 reliable information regarding the structural and intra-and intermolecular interactions is required. We have conducted studies based on the fragment molecular orbital (FMO) method for calculating the electronic structure of protein complexes and analyzing their quantitative molecular interactions. This enables us to extensively analyze the molecular interactions in residues or functional group units acting inside protein complexes. Such precise interaction data are available in the FMO database (FMODB) (https://drugdesign.riken.jp/FMODB/). Since April 2020, we have performed several FMO calculations on the structures of SARS-CoV-2 related proteins registered in the Protein Data Bank. We have published the results of 681 structures, including three structural proteins and eleven nonstructural proteins, on the COVID-19 special page (as of June 8, 2021). In this paper, we describe the entire COVID-19 special page of FMODB and discuss the calculation results for various proteins. These data not only aid the interpretation of experimentally determined structures but also the understanding of protein functions, which is useful for rational drug design for COVID-19.

show abstract

“…CTD is the dimerization domain, and its dimeric structure has been obtained by X-ray crystallography 57,58 , suggesting that it also has an RNA-binding ability. The calculation results of these structures are registered in FMODB, and representative analysis of the complex structure of NTD and single-stranded RNA (PDBID:7ACT, FMODB ID: N3Y7Q) is described below.…”

Section: Nucleocapsid (N) Proteinmentioning

confidence: 99%

Special feature of COVID-19 in FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2 related proteins

Fukuzawa

Kato

Watanabe

et al. 2021

Preprint

View full text Add to dashboard Cite

SARS-CoV-2 is the causative agent of coronavirus, globally known as COVID-19. There are ongoing researches to develop effective therapeutics and vaccines against COVID-19 using various methods. We currently conduct research based on the fragment molecular orbital (FMO) method for calculating the electronic structure of protein complexes and analyzing their quantitative molecular interactions. This enables us to extensively analyze the molecular interactions in residues or functional group units acting inside protein complexes. Such precise interaction data are available in the FMO database (FMODB). We have performed several FMO calculations on the structures of SARS-CoV-2 related proteins registered in the protein data bank and published the results of 681 structures, including three structural proteins and eleven nonstructural proteins, on the COVID-19 special page.These data not only aid the interpretation of experimentally determined structures but also the understanding of protein functions, which is useful for rational drug design for COVID-19.

show abstract

A COVID-19 antibody curbs SARS-CoV-2 nucleocapsid protein-induced complement hyperactivation

Cited by 3 publications

References 42 publications

Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests

Deep mutational scanning identifies SARS-CoV-2 Nucleocapsid escape mutations of currently available rapid antigen tests

Special feature of COVID-19 in FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2 related proteins

Special feature of COVID-19 in FMODB: Fragment molecular orbital calculations and interaction energy analysis of SARS-CoV-2 related proteins

Contact Info

Product

Resources

About