Mutations in SARS‐CoV‐2 nsp7 and nsp8 proteins and their predicted impact on replication/transcription complex structure

Reshamwala, Shamlan M. S.; Likhite, Vishakha; Degani, Mariam S.; Deb, Shalini S.; Noronha, Santosh

doi:10.1002/jmv.26791

Cited by 37 publications

(42 citation statements)

References 25 publications

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“…Interestingly, the P323L mutated RdRp appears exhibit an increased ability to bind to remdesivir which is used as an antiviral drug against Covid-19 [53], meaning this mutation does not render remdesivir less effective. Since RdRp forms a complex with NSP7 and NSP8, mutants in the latter two proteins were investigated as well [54]. Mutations in NSP7 at positions 25 and 26 (S25L; S26F; Fig.…”

Section: Hot Spot Mutationsmentioning

confidence: 99%

Variants of SARS CoV-2: mutations, transmissibility, virulence, drug resistance, and antibody/vaccine sensitivity

Prü¹

2022

Front. Biosci. (Landmark Ed)

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Severe acute respiratory syndrom coronavirus-2 (SARS CoV-2) is the causative agent of coronavirus disease-19 which has been designated a worldwide pandemic by the World Health Organization on March 11, 2020. Since that time, the virus has mutated and an assortment of variants have been successful at establishing themselves in the human population. This review article describes the SARS CoV-2 genome, hot spot mutations, variants, and then focuses on the Delta variant, finishing up with an update on the Omicron variant. The genome encompasses 11 open reading frames, one of which encodes the spike or S protein that has been the target for vaccines and some of the drugs because of its role in attachment to the human host cell, as well as antibodies. Mutations in the S protein that are common among several of the variants include D614G that increases transmissibility and viral load and is often associated with P323L on the RNA dependent RNA polymerase. N501Y is a mutation in the receptor binding domain of the S protein that increases binding to the ACE-2 receptor on the human host cells by 10 fold. The discussed variants carry combinations of these and other mutations and are classified by the World Health Organization as variants of concern, variants of interest, and variants under monitoring. All variants are characterized by increased transmissibility (relative to the original SARS CoV-2), which is the reason for their ability to establish themselves. Several but not all variants are more resistant to antiviral drugs and less susceptible to antibodies/vaccines. The Delta variant that dominated the world until November 2021 causes an increased risk for hospitalization and death, but is still very susceptible to the current vaccines. The most recent variant, Omicron, is characterized by increased transmissibility and decreased antibody susceptibility.

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Section: Hot Spot Mutationsmentioning

confidence: 99%

Variants of SARS CoV-2: mutations, transmissibility, virulence, drug resistance, and antibody/vaccine sensitivity

Prü¹

2022

Front. Biosci. (Landmark Ed)

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“…These three NSP forms a trimeric RdRp-NSP7-NSP8 super-complex [80], the basic minimal machinery required for nucleotide polymerization [79]. Mutations in NSP7 or NSP8 are associated with mutations of NSP12, and they might therefore show altered super-complex formation affecting the viral replication, infectivity, and pathogenicity [81]. Since NSP7 has less significance when unbound, few studies have been conducted on its structure.…”

Section: Non-structural Protein 7 (Nsp7)mentioning

confidence: 99%

Identification of intrinsically disorder regions in non-structural proteins of SARS-CoV-2: New insights into drug and vaccine resistance

et al. 2022

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The outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in December 2019 and caused coronavirus disease 2019 (COVID-19), which causes pneumonia and severe acute respiratory distress syndrome. It is a highly infectious pathogen that promptly spread. Like other beta coronaviruses, SARS-CoV-2 encodes some non-structural proteins (NSPs), playing crucial roles in viral transcription and replication. NSPs likely have essential roles in viral pathogenesis by manipulating many cellular processes. We performed a sequence-based analysis of NSPs to get insights into their intrinsic disorders, and their functions in viral replication were annotated and discussed in detail. Here, we provide newer insights into the structurally disordered regions of SARS-CoV-2 NSPs. Our analysis reveals that the SARS-CoV-2 proteome has a chunk of the disordered region that might be responsible for increasing its virulence. In addition, mutations in these regions are presumably responsible for drug and vaccine resistance. These findings suggested that the structurally disordered regions of SARS-CoV-2 NSPs might be invulnerable in COVID-19.

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“…The nsp12 mutation P323L 19 coevolved with the globally dominating spike protein mutation D614G 20 , is found predominantly in severely affected patients 21 and is predicted based on the structure to stabilize nsp12 association with nsp8a 20,22 . In contrast, the nsp7 mutation S25L is predicted to destabilize nsp7 binding to nsp8a 22 and the nsp7 mutation L71F, which is associated with severe COVID-19 23 , may destabilize binding of the nsp7 C-terminal region to nsp8b. This suggests that mutations in RdRp subunits can influence the relative stabilities of the RdRp monomer and dimer.…”

Section: Figurementioning

confidence: 99%

Dimeric form of SARS-CoV-2 polymerase

Jochheim

Tegunov

Hillen

et al. 2021

Preprint

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The coronavirus SARS-CoV-2 uses an RNA-dependent RNA polymerase (RdRp) to replicate and transcribe its genome. Structures of the RdRp revealed a monomeric enzyme composed of the catalytic subunit nsp12, two copies of subunit nsp8, and one copy of subunit nsp7. Here we report an alternative, dimeric form of the coronavirus polymerase and resolve its structure at 4.8 Å resolution. In this structure, the two RdRps contain only one copy of nsp8 and dimerize via their nsp7 subunits to adopt an antiparallel arrangement. We speculate that the RdRp dimer facilitates template switching during production of sub-genomic RNAs for transcription.

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Mutations in SARS‐CoV‐2 nsp7 and nsp8 proteins and their predicted impact on replication/transcription complex structure

Cited by 37 publications

References 25 publications

Variants of SARS CoV-2: mutations, transmissibility, virulence, drug resistance, and antibody/vaccine sensitivity

Variants of SARS CoV-2: mutations, transmissibility, virulence, drug resistance, and antibody/vaccine sensitivity

Identification of intrinsically disorder regions in non-structural proteins of SARS-CoV-2: New insights into drug and vaccine resistance

Dimeric form of SARS-CoV-2 polymerase

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