SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics

Gupta, Ruchir; Charron, Jacob; Stenger, Cynthia L.; Painter, Jared; Steward, Hunter; Cook, Taylor W; Faber, William E.; Frisch, Austin; Lind, Eric; Bauss, Jacob; Li, Xiaopeng; Sirpilla, Olivia; Soehnlen, Xavier; Underwood, Adam; Hinds, David A.; Morris, Michele; Lamb, Neil E.; Carcillo, Joseph A.; Bupp, Caleb; Uhal, Bruce D.; Rajasekaran, Surender; Prokop, Jeremy W.

doi:10.1074/jbc.ra120.014873

Cited by 41 publications

(37 citation statements)

References 53 publications

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“…24 The recent development of the Viral Integrated Structural Evolution Dynamic Database (VIStEDD) should help further elucidate the viral proteome dynamics and their interaction with host cell receptors. 25 Respiratory viruses with monobasic cleavage sites typically have an expression profile confined to the aerodigestive tract. Viral replication is limited to these organs as the cleavage site is cleaved by few cellular proteases, restricting viral growth to these limited areas.…”

Section: Tmprss2 and Viral Entrymentioning

confidence: 99%

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Gene of the month:TMPRSS2(transmembrane serine protease 2)

Thunders

Delahunt

2020

J Clin Pathol

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Transmembrane serine protease 2 is encoded by the TMPRSS2 gene. The gene is widely conserved and has two isoforms, both being autocatalytically activated from the inactive zymogen form. A fusion gene between the TMPRSS2 gene and ERG (erythroblast-specific-related gene), an oncogenic transcription factor, is the most common chromosomal aberration detected in prostate cancer, responsible for driving carcinogenesis. The other key role of TMPRSS2 is in priming the viral spike protein which facilitates viral entry essential for viral infectivity. The protease activates a diverse range of viruses. Both SARS-CoV and SARS-CoV-2 (COVID-19) use angiotensin-converting enzyme 2 (ACE2) and TMPRSS2 to facilitate entry to cells, but with SARS-CoV-2 human-to-human transmission is much higher than SARS-CoV. As TMPRSS2 is expressed outside of the lung, and can therefore contribute to extrapulmonary spread of viruses, it warrants further exploration as a potential target for limiting viral spread and infectivity.

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Section: Tmprss2 and Viral Entrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gene of the month:TMPRSS2(transmembrane serine protease 2)

Thunders

Delahunt

2020

J Clin Pathol

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“…Also, these residues are the most conserved residues of N protein according to multiple sequence alignment results obtained from ESPript 3.0 (Robert & Gouet, 2014) ( Figure S3, supplementary material). According to a recent study, the amino acids, 331-333 were the most conserved yet dynamic site of N and involved in the multimerization of N protein (Gupta et al, 2020). The multimeric structure of N revealed that the conserved amino acids Val270, Phe274, Arg277, Asn285, Gly287, Phe286, and Asp288 are clustered and surface exposed, and thus could contribute to protein-protein interactions.…”

Section: Evaluating the Stability And Conformational Dynamics Of Ctd-mentioning

confidence: 99%

Targeting SARS-CoV-2 nucleocapsid oligomerization: Insights from molecular docking and molecular dynamics simulations

Ahamad

Gupta

Kumar

2020

Journal of Biomolecular Structure and Dynamics

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The outbreak of COVID-19 caused by SARS-CoV-2 virus continually led to infect a large population worldwide. Currently, there is no specific viral protein-targeted therapeutics. The Nucleocapsid (N) protein of the SARS-CoV-2 virus is necessary for viral RNA replication and transcription. The C-terminal domain of N protein (CTD) involves in the self-assembly of N protein into a filament that is packaged into new virions. In this study, the CTD (PDB ID: 6WJI) was targeted for the identification of possible inhibitors of oligomerization of N protein. Herein, multiple computational approaches were employed to explore the potential mechanisms of binding and inhibitor activity of five antiviral drugs toward CTD. The five anti-N drugs studied in this work are 4E1RCat, Silmitasertib, TMCB, Sapanisertib, and Rapamycin. Among the five drugs, 4E1RCat displayed highest binding affinity (-10.95 kcal/mol), followed by rapamycin (-8.91 kcal/mol), silmitasertib (-7.89 kcal/mol), TMCB (-7.05 kcal/mol), and sapanisertib (-6.14 kcal/mol). Subsequently, stability and dynamics of the protein-drug complex were examined with molecular dynamics (MD) simulations. Overall, drug binding increases the stability of the complex with maximum stability observed in the case of 4E1RCat. The CTD-drug complex systems behave differently in terms of the free energy landscape and showed differences in population distribution. Overall, the MD simulation parameters like RMSD, RMSF, Rg, hydrogen bonds analysis, PCA, FEL, and DCCM analysis indicated that 4E1RCat and TMCB complexes were more stable as compared to silmitasertib and sapanisertib and thus could act as effective drug compounds against CTD.

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“…Structural level insights for coronavirus proteins are surprisingly deficient of human interaction partners. 10 A few of these proteins have been targeted for interaction assessments, such as the nucleocapsid protein 24 , 25 (shown below). It has been speculated that the understanding of virus–host interactions represents a major untapped potential of viral inhibitors.…”

Section: Sars-cov-2 Human Protein Interactionsmentioning

confidence: 99%

SARS-CoV-2-Encoded Proteome and Human Genetics: From Interaction-Based to Ribosomal Biology Impact on Disease and Risk Processes

et al. 2020

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SARS-CoV-2 (COVID-19) has infected millions of people worldwide, with lethality in hundreds of thousands. The rapid publication of information, both regarding the clinical course and the viral biology, has yielded incredible knowledge of the virus. In this review, we address the insights gained for the SARS-CoV-2 proteome, which we have integrated into the Viral Integrated Structural Evolution Dynamic Database, a publicly available resource. Integrating evolutionary, structural, and interaction data with human proteins, we present how the SARS-CoV-2 proteome interacts with human disorders and risk factors ranging from cytokine storm, hyperferritinemic septic, coagulopathic, cardiac, immune, and rare disease-based genetics. The most noteworthy human genetic potential of SARS-CoV-2 is that of the nucleocapsid protein, where it is known to contribute to the inhibition of the biological process known as nonsense-mediated decay. This inhibition has the potential to not only regulate about 10% of all biological transcripts through altered ribosomal biology but also associate with viral-induced genetics, where suppressed human variants are activated to drive dominant, negative outcomes within cells. As we understand more of the dynamic and complex biological pathways that the proteome of SARS-CoV-2 utilizes for entry into cells, for replication, and for release from human cells, we can understand more risk factors for severe/lethal outcomes in patients and novel pharmaceutical interventions that may mitigate future pandemics.

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SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics

Cited by 41 publications

References 53 publications

Gene of the month:TMPRSS2(transmembrane serine protease 2)

Gene of the month:TMPRSS2(transmembrane serine protease 2)

Targeting SARS-CoV-2 nucleocapsid oligomerization: Insights from molecular docking and molecular dynamics simulations

SARS-CoV-2-Encoded Proteome and Human Genetics: From Interaction-Based to Ribosomal Biology Impact on Disease and Risk Processes

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