Insights into SARS-CoV transcription and replication from the structure of the nsp7–nsp8 hexadecamer

Zhai, Yujia; Sun, Fei; Li, Xuemei; Pang, Hai; Xu, Xiaoling; Bartlam, Mark; Rao, Zihe

doi:10.1038/nsmb999

Cited by 270 publications

(440 citation statements)

References 43 publications

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“…Zihe Rao and colleagues have determined the first crystal structure of a complex between two non-structural proteins, nsp7 and nsp8 (Fig. 6) [120]. Eight copies of nsp7 and eight copies of nsp8 together form an intricate scaffold that resembles a hollow cylinder.…”

Section: Non-structural or Replicase Proteinsmentioning

confidence: 98%

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Yang¹,

Bartlam²,

Rao

2006

CPD

Self Cite

166

143

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Coronaviruses (CoVs), a genus containing about 26 known species to date, cause highly prevalent diseases and are often severe or fatal in humans and animals. In 2003, a previously unknown coronavirus was identified to be the etiological agent of a global outbreak of a form of life-threatening pneumonia called severe acute respiratory syndrome (SARS). No efficacious therapy is currently available, and vaccines and drugs are under development to prevent SARS-CoV infection in many countries. The CoV main protease (M(pro)), which plays a pivotal role in viral gene expression and replication through a highly complex cascade involving the proteolytic processing of replicase polyproteins, is an attractive target for drug design. This review summarizes the recent advances in biological and structural studies, together with development of inhibitors targeting CoV M(pro)s. It is expected that inhibitors targeting CoV M(pro)s could be developed into wide-spectrum antiviral drugs against existing and possible future emerging CoV-associated diseases.

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Section: Non-structural or Replicase Proteinsmentioning

confidence: 98%

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Yang¹,

Bartlam²,

Rao

2006

CPD

Self Cite

166

143

View full text Add to dashboard Cite

show abstract

“…The tunnel traversing the hexamer is too narrow to accommodate an RNA substrate, a feature proposed for the nsp7-nsp8 complex (11). Moreover, Glu-44 side chains protrude into the tunnel, rendering its surface negatively charged, a feature that is not compatible with RNA binding.…”

mentioning

confidence: 92%

“…1 and 2). Furthermore, crystal structures of five nsps (or subdomains thereof) have been reported: the ADP-ribose-1Љ-phosphatase macro domain of nsp3, the main protease nsp5, the RNA-binding protein nsp9, and the complex of nsp7-nsp8, a proposed processivity factor for the RNA-dependent RNA polymerase nsp12 (8)(9)(10)(11)(12). nsp13 is a superfamily 1 helicase (7, 13), whereas nsp14, nsp15, and nsp16 have been predicted or confirmed to harbor 3Ј-5Ј exonuclease, endonuclease, and 2Ј-O-ribose methyltransferase activities, respectively (7,(13)(14)(15).…”

mentioning

confidence: 99%

Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family

Ricagno¹,

Egloff²,

Ulferts

et al. 2006

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

172

241

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The Ϸ30-kb coronavirus (؉)RNA genome is replicated and transcribed by a membrane-bound replicase complex made up of 16 viral nonstructural proteins (nsp) with multiple enzymatic activities. The complex includes an RNA endonuclease, NendoU, that is conserved among nidoviruses but no other RNA virus, making it a genetic marker of this virus order. NendoU (nsp15) is a Mn 2؉ -dependent, uridylate-specific enzyme, which leaves 2-3-cyclic phosphates 5 to the cleaved bond. Neither biochemical nor sequence homology criteria allow a classification of nsp15 into existing endonuclease families. Here, we report the crystal structure of the severe acute respiratory syndrome coronavirus nsp15 at 2.6-Å resolution. Nsp15 exhibits a unique fold and assembles into a toric hexamer with six potentially active, peripheric catalytic sites. The structure and the spatial arrangement of the catalytic residues into an RNase A-like active site define a separate endonuclease family, endoU, and represent another spectacular example of convergent evolution toward an enzymatic function that is critically involved in the coronavirus replication cycle.endonuclease ͉ severe acute respiratory syndrome ͉ nidovirus ͉ replication

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“…3) invites comparisons with the sliding clamp proteins proliferating cell nuclear antigen (19) and ␤-clamp (20), and with the SARS-CoV nsp7-nsp8 hexadecamer (21). Like RdgC, these have a ring structure with a hole lined with positive potential and an outer negative surface.…”

Section: Resultsmentioning

confidence: 99%

Ring Structure of the Escherichia coli DNA-binding Protein RdgC Associated with Recombination and Replication Fork Repair

Briggs

McEwan

et al. 2007

Journal of Biological Chemistry

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The DNA-binding protein, RdgC, is associated with recombination and replication fork repair in Escherichia coli and with the virulence-associated, pilin antigenic variation mediated by RecA and other recombination proteins in Neisseria species. We solved the structure of the E. coli protein and refined it to 2.4 Å . RdgC crystallizes as a dimer with a head-to-head, tail-to-tail organization forming a ring with a 30 Å diameter hole at the center. The protein fold is unique and reminiscent of a horseshoe with twin gates closing the open end. The central hole is lined with positively charged residues and provides a highly plausible DNA binding channel consistent with the nonspecific mode of binding detected in vitro and with the ability of RdgC to modulate RecA function in vivo.

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Insights into SARS-CoV transcription and replication from the structure of the nsp7–nsp8 hexadecamer

Cited by 270 publications

References 43 publications

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Drug Design Targeting the Main Protease, the Achilles Heel of Coronaviruses

Crystal structure and mechanistic determinants of SARS coronavirus nonstructural protein 15 define an endoribonuclease family

Ring Structure of the Escherichia coli DNA-binding Protein RdgC Associated with Recombination and Replication Fork Repair

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