Structural basis for the multimerization of nonstructural protein nsp9 from SARS-CoV-2

Zhang, Changhui; Li, Li; Yang, Yan; He, Jun; Chen, Cheng; Su, Dan

doi:10.1186/s43556-020-00005-0

Cited by 26 publications

(46 citation statements)

References 31 publications

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“…The complex is assembled by Nsp7‐(Nsp8) 2 ‐Nsp12‐(Nsp13) 2 ‐RNA and a single RNA‐binding protein, Nsp9, which is necessary for RTC function. [ 4 ] Although Nsp9 has a strong tendency to oligomerize, [ 5–7 ] within the RTC it appears to be in a monomeric state. [ 8 ] As a monomer, Nsp9 interacts with the Nsp12 (RdRp) NiRAN catalytic domain, which has nucleoside monophosphate (NMP) transferase activity, leading to the covalent attachment of a nucleoside monophosphate to the evolutionarily conserved Nsp9 amino terminus, a critical step in the initiation of viral replication.…”

Section: Introductionmentioning

confidence: 99%

NMR‐Based Analysis of Nanobodies to SARS‐CoV‐2 Nsp9 Reveals a Possible Antiviral Strategy Against COVID‐19

et al. 2021

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Following the entry into the host cell, SARS‐CoV‐2 replication is mediated by the replication transcription complex (RTC) assembled through a number of nonstructural proteins (Nsps). A monomeric form of Nsp9 is particularly important for RTC assembly and function. In the present study, 136 unique nanobodies targeting Nsp9 are generated. Several nanobodies belonging to different B‐cell lineages are expressed, purified, and characterized. Results from immunoassays applied to purified Nsp9 and neat saliva from coronavirus disease (COVID‐19) patients show that these nanobodies effectively and specifically recognize both recombinant and endogenous Nsp9. Nuclear magnetic resonance analyses supported by molecular dynamics reveal a composite Nsp9 oligomerization pattern and demonstrate that both nanobodies stabilize the tetrameric form of wild‐type Nsp9 also identifying the epitopes on the tetrameric assembly. These results can have important implications in the potential use of these nanobodies to combat viral replication.

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Section: Introductionmentioning

confidence: 99%

NMR‐Based Analysis of Nanobodies to SARS‐CoV‐2 Nsp9 Reveals a Possible Antiviral Strategy Against COVID‐19

et al. 2021

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“…The monomer is composed of seven β-strands (β1-β7), an N-terminal β7 extension, and a C-terminal α-helix with a conserved “GxxxG” motif (Fig. S5) (Littler, 2020; Zhang, 2020). Its dimerization occurs via the “GxxxG” motif present also in SARS-CoV Nsp9 (Sutton, 2004; Littler, 2020) and by the N-terminal β7 extension (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Its dimerization occurs via the “GxxxG” motif present also in SARS-CoV Nsp9 (Sutton, 2004; Littler, 2020) and by the N-terminal β7 extension (Fig. S5) (Littler, 2020; Zhang, 2020). Zhang et al (2020) reported a SARS-CoV-2 nsp9 homotetramer structure with an interface composed mainly of β5 and three connection loops.…”

Section: Resultsmentioning

confidence: 99%

Analysis of the Dynamics and Distribution of SARS-CoV-2 Mutations and its Possible Structural and Functional Implications

et al. 2020

Preprint

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After eight months of the pandemic declaration, COVID-19 has not been globally controlled. Several efforts to control SARS-CoV-2 dissemination are still running including vaccines and drug treatments. The effectiveness of these procedures depends, in part, that the regions to which these treatments are directed do not vary considerably. Although, it is known that the mutation rate of SARS-CoV-2 is relatively low it is necessary to monitor the adaptation and evolution of the virus in the different stages of the pandemic. Thus, identification, analysis of the dynamics, and possible functional and structural implication of mutations are relevant. Here, we first estimate the number of COVID-19 cases with a virus with a specific mutation and then calculate its global relative frequency (NRFp). Using this approach in a dataset of 100 924 genomes from GISAID, we identified 41 mutations to be present in viruses in an estimated number of 750 000 global COVID-19 cases (0.03 NRFp). We classified these mutations into three groups: high-frequent, low-frequent non-synonymous, and low-frequent synonymous. Analysis of the dynamics of these mutations by month and continent showed that high-frequent mutations appeared early in the pandemic, all are present in all continents and some of them are almost fixed in the global population. On the other hand, low-frequent mutations (non-synonymous and synonymous) appear late in the pandemic and seems to be at least partially continent-specific. This could be due to that high-frequent mutation appeared early when lockdown policies had not yet been applied and low-frequent mutations appeared after lockdown policies. Thus, preventing global dissemination of them. Finally, we present a brief structural and functional review of the analyzed ORFs and the possible implications of the 25 identified non-synonymous mutations.

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“…Apart from creating complex with NSP7, NSP8 creates complex with accessory protein ORF6 also ( Kumar et al, 2007 ). Both NSP9 and NSP10 are small non-enzymatic proteins and assist in the function of NSP12 ( Zhang et al, 2020 ). NSP10 also interacts with NSP14 and NSP16.…”

Section: Introductionmentioning

confidence: 99%

Structural and Drug Screening Analysis of the Non-structural Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Virus Extracted From Indian Coronavirus Disease 2019 Patients

et al. 2021

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The novel coronavirus 2 (nCoV2) outbreaks took place in December 2019 in Wuhan City, Hubei Province, China. It continued to spread worldwide in an unprecedented manner, bringing the whole world to a lockdown and causing severe loss of life and economic stability. The coronavirus disease 2019 (COVID-19) pandemic has also affected India, infecting more than 10 million till 31st December 2020 and resulting in more than a hundred thousand deaths. In the absence of an effective vaccine, it is imperative to understand the phenotypic outcome of the genetic variants and subsequently the mode of action of its proteins with respect to human proteins and other bio-molecules. Availability of a large number of genomic and mutational data extracted from the nCoV2 virus infecting Indian patients in a public repository provided an opportunity to understand and analyze the specific variations of the virus in India and their impact in broader perspectives. Non-structural proteins (NSPs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) virus play a major role in its survival as well as virulence power. Here, we provide a detailed overview of the SARS-CoV2 NSPs including primary and secondary structural information, mutational frequency of the Indian and Wuhan variants, phylogenetic profiles, three-dimensional (3D) structural perspectives using homology modeling and molecular dynamics analyses for wild-type and selected variants, host-interactome analysis and viral–host protein complexes, and in silico drug screening with known antivirals and other drugs against the SARS-CoV2 NSPs isolated from the variants found within Indian patients across various regions of the country. All this information is categorized in the form of a database named, Database of NSPs of India specific Novel Coronavirus (DbNSP InC), which is freely available at http://www.hpppi.iicb.res.in/covid19/index.php.

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Structural basis for the multimerization of nonstructural protein nsp9 from SARS-CoV-2

Cited by 26 publications

References 31 publications

NMR‐Based Analysis of Nanobodies to SARS‐CoV‐2 Nsp9 Reveals a Possible Antiviral Strategy Against COVID‐19

NMR‐Based Analysis of Nanobodies to SARS‐CoV‐2 Nsp9 Reveals a Possible Antiviral Strategy Against COVID‐19

Analysis of the Dynamics and Distribution of SARS-CoV-2 Mutations and its Possible Structural and Functional Implications

Structural and Drug Screening Analysis of the Non-structural Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Virus Extracted From Indian Coronavirus Disease 2019 Patients

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