5eyi
From Proteopedia
Structure of PRRSV apo-NSP11 at 2.16A
Structural highlights
FunctionRPOA_PRRS1 The replicase polyprotein 1ab is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products. Nsp1 is essential for viral subgenomic mRNA synthesis. Nsp1-alpha inhibits IFN-beta production. Counteracts the action of NF-kappaB by decreasing the phosphorylation of IkappaB-alpha, such that the degradation of IkappaB-alpha is suppressed. This leads to the blockage of NF-kappaB nuclear translocation and thus interference of NF-kappaB activation. Also seems to inhibit IRF3-dependent pathways (By similarity). Nsp2 cysteine proteinase which cleaves the nsp2/nsp3 site in the polyprotein. Also displays deubiquitinating and deISGylase activities. The deubiquitinating activity cleaves both ubiquitinated and ISGylated products and may therefore regulate ubiquitin and ISG15 dependent host innate immunity. Deubiquitinates host NFKBIA, thereby interfering with NFKBIA degradation and impairing subsequent NF-kappa-B activation (By similarity). The 3C-like serine proteinase chain is responsible for the majority of cleavages as it cleaves the C-terminus of the polyprotein. The helicase chain, which contains a zinc finger structure, displays RNA and DNA duplex-unwinding activities with 5' to 3' polarity. Publication Abstract from PubMedEndoribonuclease (NendoU) is unique and conserved as a major genetic marker in nidoviruses that infect vertebrate hosts. Arterivirus non-structural protein (nsp) 11 was shown to have NendoU activity and play essential roles in the viral life cycle. Here, we report three crystal structures of porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV) nsp11 mutants. The structures of arterivirus nsp11 contain two conserved compact domains: N-terminal domain (NTD) and C-terminal domain (CTD). The structures of PRRSV and EAV endoribonucleases are similar and conserved in the arterivirus, but they are greatly different from that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoV) representing important human pathogens in the Nidovirales order. The catalytic center of NendoU activity is located in the CTD, where a positively charged groove is next to the key catalytic residues conserved in nidoviruses. Although the NTD is nearly identical, the catalytic region of the arterivirus nsp11 family proteins is remarkably flexible, and the oligomerization may be concentration-dependent. In summary, our structures provide new insight into this key multifunctional NendoU family of proteins and lay a foundation for better understanding of the molecular mechanism and antiviral drug development. IMPORTANCE: Porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus are two major members of the arterivirus family. PRRSV, a leading swine pathogen, causes reproductive failure in breeding stock and respiratory tract illness in young pigs. Due to the lack of a suitable vaccine or effective drug treatment and the quick spread of these viruses, infected animals either die quickly or must be culled. PRRSV costs the swine industry around $644 million annually in the USA and almost 1.5b[euro] in Europe every year. To find a way to combat these viruses, we focused on the essential viral non-structural protein (nsp) 11. Nsp11 is associated with multiple functions such as RNA-processing and suppressing the infected host innate immunity system. The three solved structures in this study provide new insight into the molecular mechanisms of this crucial protein family and will benefit the development of new treatments against these deadly viruses. Structural biology of the arterivirus nsp11 endoribonucleases.,Zhang M, Li X, Deng Z, Chen Z, Liu Y, Gao Y, Wu W, Chen Z J Virol. 2016 Oct 19. pii: JVI.01309-16. PMID:27795409[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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