Structural Basis of Severe Acute Respiratory Syndrome Coronavirus ADP-Ribose-1″-Phosphate Dephosphorylation by a Conserved Domain of nsP3

Saikatendu, Kumar Singh; Joseph, Jeremiah S.; Subramanian, Vanitha; Clayton, Thomas; Griffith, Mark T.; Moy, Kin; Velasquez, Jeffrey; Neuman, Benjamin W.; Buchmeier, Michael J.; Stevens, Raymond C.; Kühn, Peter

doi:10.1016/j.str.2005.07.022

Cited by 195 publications

(229 citation statements)

References 64 publications

(60 reference statements)

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“…The presence of a YbiA family NADAR domain in the polyproteins of RNA viruses is also of interest in this regard because it mirrors the earlier reported occurrence of Macro and 2H phosphoesterases (which hydrolyze 2 0 ,3 0 -cyclic phosphates and Appr>p) in diverse RNA and retroviruses. 60,62,63 Thus, it is conceivable that the NADAR domains also perform functions comparable to these enzymes in the above viruses. Finally, the presence of YbiA-like NADAR domains (including phage T4 gp33.3-like proteins) in NCLDVs and several bacteriophages may also be linked to their possession of functionally linked RNA-repair enzymes that include the 2H phosphoesterases and RNA ligases.…”

Section: à14mentioning

confidence: 99%

Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

Souza

Aravind

2012

Mol. BioSyst.

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Nicotinamide adenine dinucleotide (NAD) is a ubiquitous cofactor participating in numerous redox reactions. It is also a substrate for regulatory modifications of proteins and nucleic acids via the addition of ADP-ribose moieties or removal of acyl groups by transfer to ADP-ribose. In this study, we use in-depth sequence, structure and genomic context analysis to uncover new enzymes and substrate-binding proteins in NAD-utilizing metabolic and macromolecular modification systems. We predict that Escherichia coli YbiA and related families of domains from diverse bacteria, eukaryotes, large DNA viruses and single strand RNA viruses are previously unrecognized components of NAD-utilizing pathways that probably operate on ADP-ribose derivatives. Using contextual analysis we show that some of these proteins potentially act in RNA repair, where NAD is used to remove 2 0 -3 0 cyclic phosphodiester linkages. Likewise, we predict that another family of YbiA-related enzymes is likely to comprise a novel NAD-dependent ADP-ribosylation system for proteins, in conjunction with a previously unrecognized ADP-ribosyltransferase. A similar ADP-ribosyltransferase is also coupled with MACRO or ADP-ribosylglycohydrolase domain proteins in other related systems, suggesting that all these novel systems are likely to comprise pairs of ADP-ribosylation and ribosylglycohydrolase enzymes analogous to the DraG-DraT system, and a novel group of bacterial polymorphic toxins. We present evidence that some of these coupled ADP-ribosyltransferases/ribosylglycohydrolases are likely to regulate certain restriction modification enzymes in bacteria. The ADP-ribosyltransferases found in these, the bacterial polymorphic toxin and host-directed toxin systems of bacteria such as Waddlia also throw light on the evolution of this fold and the origin of eukaryotic polyADP-ribosyltransferases and NEURL4-like ARTs, which might be involved in centrosomal assembly. We also infer a novel biosynthetic pathway that might be involved in the synthesis of a nicotinate-derived compound in conjunction with an asparagine synthetase and AMPylating peptide ligase. We use the data derived from this analysis to understand the origin and early evolutionary trajectories of key NAD-utilizing enzymes and present targets for future biochemical investigations.

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Section: à14mentioning

confidence: 99%

Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

Souza

Aravind

2012

Mol. BioSyst.

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“…Although successful containment measures halted the spread of the virus, the possibility of future outbreaks of both SARS-CoV and related viruses warrants a continued search for new, effective antivirals. Replication of the SARS-CoV genome is mediated by nonstructural proteins (nsps [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]) that assemble to generate the multifunctional, membrane-associated replicase complex. The nsps are encoded in two ORFs (ORF1a and ORF1b) encompassing Ͼ20 kb of the 5Ј-most region of the RNA genome.…”

mentioning

confidence: 99%

“…nsp3 also houses a recently characterized phosphatase (11,12), a transmembrane domain (10), a conserved acidic domain, and a Y domain of unknown function (Fig. 1).…”

mentioning

confidence: 99%

Severe acute respiratory syndrome coronavirus papain-like protease: Structure of a viral deubiquitinating enzyme

Ratia

Saikatendu²,

Santarsiero

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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385

531

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Replication of severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) requires proteolytic processing of the replicase polyprotein by two viral cysteine proteases, a chymotrypsin-like protease (3CLpro) and a papain-like protease (PLpro). These proteases are important targets for development of antiviral drugs that would inhibit viral replication and reduce mortality associated with outbreaks of SARS-CoV. In this work, we describe the 1.85-Å crystal structure of the catalytic core of SARS-CoV PLpro and show that the overall architecture adopts a fold closely resembling that of known deubiquitinating enzymes. Key features, however, distinguish PLpro from characterized deubiquitinating enzymes, including an intact zinc-binding motif, an unobstructed catalytically competent active site, and the presence of an intriguing, ubiquitinlike N-terminal domain. To gain insight into the active-site recognition of the C-terminal tail of ubiquitin and the related LXGG motif, we propose a model of PLpro in complex with ubiquitinaldehyde that reveals well defined sites within the catalytic cleft that help to account for strict substrate-recognition motifs.membrane-associated protease ͉ ubiquitin-like domain

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“…Nsp3 is a large multidomain protein of 1922 amino acids that is yielded by proteolytic cleavage of the pp1a polyprotein at two sites by the papain-like protease (PL pro ). Two crystal structures of the functional enzymatic domains of nsp3 have been determined: the 'X' domain with proposed ADP-ribose-1 00 -phosphate dephosphorylation (ADRP) activity (Saikatendu et al, 2005;Egloff et al, 2006) and the papain-like protease (PL pro ) domain (Ratta et al, 2006). The 'X' domain, also known as the ADRP domain, is conserved among all CoV (Putics et al, 2005) and is structurally related to macro-H2A-like fold proteins (Fig.…”

Section: The Replicase Complexmentioning

confidence: 99%

The search for a structural basis for therapeutic intervention against the SARS coronavirus

2007

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The 2003 outbreak of severe acute respiratory syndrome (SARS), caused by a previously unknown coronavirus called SARS-CoV, had profound social and economic impacts worldwide. Since then, structure-function studies of SARSCoV proteins have provided a wealth of information that increases our understanding of the underlying mechanisms of SARS. While no effective therapy is currently available, considerable efforts have been made to develop vaccines and drugs to prevent SARS-CoV infection. In this review, some of the notable achievements made by SARS structural biology projects worldwide are examined and strategies for therapeutic intervention are discussed based on available SARS-CoV protein structures. To date, 12 structures have been determined by X-ray crystallography or NMR from the 28 proteins encoded by SARS-CoV. One key protein, the SARS-CoV main protease (M pro ), has been the focus of considerable structure-based drug discovery efforts. This article highlights the importance of structural biology and shows that structures for drug design can be rapidly determined in the event of an emerging infectious disease.

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Structural Basis of Severe Acute Respiratory Syndrome Coronavirus ADP-Ribose-1″-Phosphate Dephosphorylation by a Conserved Domain of nsP3

Cited by 195 publications

References 64 publications

Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

Identification of novel components of NAD-utilizing metabolic pathways and prediction of their biochemical functions

Severe acute respiratory syndrome coronavirus papain-like protease: Structure of a viral deubiquitinating enzyme

The search for a structural basis for therapeutic intervention against the SARS coronavirus

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