Molecular Basis for ADP-ribose Binding to the Macro-X Domain of SARS-CoV-2 Nsp3

Frick, David N.; Virdi, Rajdeep S; Vuksanovic, Nemanja; Dahal, Narayan; Silvaggi, N.R.

doi:10.1101/2020.03.31.014639

Cited by 7 publications

(11 citation statements)

References 37 publications

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“…Intriguingly, the binding affinity of SARS-CoV-2 Mac-1 for ADPr was comparable to that of MERS-CoV Mac-1 (−9.70 kcal/mol). This suggest that SARS-CoV-2 may evade host antiviral ADPr activity similar to that of the highly pathogenic MERS-CoV [50].…”

Section: A D E 3 4 7 6 5 -B a T-s A R S -C O V -H K U 3 -8 A Ia 6 mentioning

confidence: 94%

Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity

et al. 2020

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The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading fast worldwide. There is a pressing need to understand how the virus counteracts host innate immune responses. Deleterious clinical manifestations of coronaviruses have been associated with virus-induced direct dysregulation of innate immune responses occurring via viral macrodomains located within nonstructural protein-3 (Nsp3). However, no substantial information is available concerning the relationship of macrodomains to the unusually high pathogenicity of SARS-CoV-2. Here, we show that structural evolution of macrodomains may impart a critical role to the unique pathogenicity of SARS-CoV-2. Using sequence, structural, and phylogenetic analysis, we identify a specific set of historical substitutions that recapitulate the evolution of the macrodomains that counteract host immune response. These evolutionary substitutions may alter and reposition the secondary structural elements to create new intra-protein contacts and, thereby, may enhance the ability of SARS-CoV-2 to inhibit host immunity. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection‐driven epistasis in protein evolution. Our findings warrant further characterization of macrodomain-specific evolutionary substitutions in in vitro and in vivo models to determine their inhibitory effects on the host immune system.

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Section: A D E 3 4 7 6 5 -B a T-s A R S -C O V -H K U 3 -8 A Ia 6 mentioning

confidence: 94%

Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity

et al. 2020

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“…Whilst not essential, mutation of SARS-CoV Nsp3-macrodomain X attenuated viral loads and led to enhanced interferon-α and -β production, interferon-stimulated gene activation and pro-inflammatory IL-6 and TNF signals in mice, implicating macrodomain X in dampening host innate immunity [76]. Binding of ADP-ribose and other related adenosine-derivatives is conserved by SARS-CoV-2 Nsp3-macrodomain X [78,79], with structures revealing high structural homology to the SARS-CoV Nsp3-macrodomain X ( Figure 4D) [78,80,81]. Further, ADP-ribose and AMP bound Nsp3-macrodomain X structures revealed how a hydrophobic substrate-binding pocket (comprising I23, V49, P125, V155 & F156) anchored adenine moieties whilst a conserved acidic D22 formed a high-enthalpy interaction with the adenine amine group ( Figure 4E) [78].…”

Section: Papain-like Protease Nsp3mentioning

confidence: 99%

A pocket guide on how to structure SARS-CoV-2 drugs and therapies

Littler

MacLachlan

Watson

et al. 2020

Biochemical Society Transactions

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The race to identify a successful treatment for COVID19 will be defined by fundamental research into the replication cycle of the SARS-CoV-2 virus. This has identified five distinct stages from which numerous vaccination and clinical trials have emerged alongside an innumerable number of drug discovery studies currently in development for disease intervention. Informing every step of the viral replication cycle has been an unprecedented ‘call-to-arms' by the global structural biology community. Of the 20 main SARS-CoV-2 proteins, 13 have been resolved structurally for SARS-CoV-2 with most having a related SARS-CoV and MERS-CoV structural homologue totalling some 300 structures currently available in public repositories. Herein, we review the contribution of structural studies to our understanding of the virus and their role in structure-based development of therapeutics.

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“…7 Nsp3 is a large multidomain membrane-bound protein, and its clearest role in viral replication is cleaving the rep polyprotein. 7 Although the biological role of ADP-ribose binding is still poorly understood, macro X domain is also a promising drug target. 7 Of all the structural proteins, the N protein is a highly immunogenic and abundantly expressed during infection.…”

Section: Introductionmentioning

confidence: 99%

“…7 Although the biological role of ADP-ribose binding is still poorly understood, macro X domain is also a promising drug target. 7 Of all the structural proteins, the N protein is a highly immunogenic and abundantly expressed during infection. 7 Although the SARS-CoV-2 S protein is currently being used as a leading target antigen in vaccine development the complex mechanisms of viral entry lends itself to complications in vaccine response.…”

Section: Introductionmentioning

confidence: 99%

“…7 Of all the structural proteins, the N protein is a highly immunogenic and abundantly expressed during infection. 7 Although the SARS-CoV-2 S protein is currently being used as a leading target antigen in vaccine development the complex mechanisms of viral entry lends itself to complications in vaccine response. 7 In contrast to the SARS-CoV-2 S protein, the N gene is more conserved and stable, with 90% amino acid homology and fewer mutations over time, also making it an ideal drug target.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Dynamics Reveals the Effects of Temperature on Critical SARS-CoV-2 Proteins

Morgan

Shu

2021

Preprint

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a newly identified RNA virus that causes the serious infection Coronavirus Disease 2019 (COVID-19). The incidence of COVID-19 is still increasing worldwide despite the summer heat and cool winter. However, little is known about seasonal stability of SARS-CoV-2. Herein, we employ Molecular Dynamics (MD) simulations to explore the effect of temperature on four critical SARS-CoV-2 proteins. Our work demonstrates that the spike Receptor Binding Domain (RBD), Main protease (Mpro), and nonstructural protein 3 (macro X) possesses extreme thermos-stability when subjected to temperature variations rendering them attractive drug targets. Furthermore, our findings suggest that these four proteins are well adapted to habitable temperatures on earth and are largely insensitive to cold and warm climates. Furthermore, we report that the critical residues in SARS-CoV-2 RBD were less responsive to temperature variations as compared to the critical residues in SARS-CoV. As such, extreme summer and winter climates, and the transition between the two seasons, are expected to have a negligible effect on the stability of SARS-CoV-2 which will marginally suppress transmission rates until effective therapeutics are available world-wide.

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Molecular Basis for ADP-ribose Binding to the Macro-X Domain of SARS-CoV-2 Nsp3

Cited by 7 publications

References 37 publications

Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity

Evolutionary and structural analysis of SARS-CoV-2 specific evasion of host immunity

A pocket guide on how to structure SARS-CoV-2 drugs and therapies

Molecular Dynamics Reveals the Effects of Temperature on Critical SARS-CoV-2 Proteins

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