3l2a | pdb_00003l2a

Crystal structure of Reston Ebola VP35 interferon inhibitory domain

spinqualitylabelsall models 3l2a, resolution 1.71Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3l2a is a 1 chain structure with sequence from Reston ebolavirus - Reston (1989). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.71Å Ligands: ACY, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function VP35_EBORR Acts as a polymerase cofactor in the RNA polymerase transcription and replication complex. Prevents establishment of cellular antiviral state by blocking virus-induced phosphorylation and activation of interferon regulatory factor 3 (IRF3), a transcription factor critical for the induction of interferons alpha and beta. The mechanism by which this blockage occurs remains incompletely defined, a hypothesis suggests that VP35 dsRNA-binding activity prevents activation of IRF3 by sequestering dsRNA. Also inhibits the antiviral effect mediated by the interferon-induced, double-stranded RNA-activated protein kinase EIF2AK2/PKR (By similarity). Publication Abstract from PubMed Ebolaviruses are causative agents of lethal hemorrhagic fever in humans and nonhuman primates. Among the filoviruses characterized thus far, Reston Ebola virus (REBOV) is the only Ebola virus that is nonpathogenic to humans despite the fact that REBOV can cause lethal disease in nonhuman primates. Previous studies also suggest that REBOV is less effective at inhibiting host innate immune responses than Zaire Ebola virus (ZEBOV) or Marburg virus. Virally encoded VP35 protein is critical for immune suppression, but an understanding of the relative contributions of VP35 proteins from REBOV and other filoviruses is currently lacking. In order to address this question, we characterized the REBOV VP35 interferon inhibitory domain (IID) using structural, biochemical, and virological studies. These studies reveal differences in double-stranded RNA binding and interferon inhibition between the two species. These observed differences are likely due to increased stability and loss of flexibility in REBOV VP35 IID, as demonstrated by thermal shift stability assays. Consistent with this finding, the 1.71-A crystal structure of REBOV VP35 IID reveals that it is highly similar to that of ZEBOV VP35 IID, with an overall backbone r.m.s.d. of 0.64 A, but contains an additional helical element at the linker between the two subdomains of VP35 IID. Mutations near the linker, including swapping sequences between REBOV and ZEBOV, reveal that the linker sequence has limited tolerance for variability. Together with the previously solved ligand-free and double-stranded-RNA-bound forms of ZEBOV VP35 IID structures, our current studies on REBOV VP35 IID reinforce the importance of VP35 in immune suppression. Functional differences observed between REBOV and ZEBOV VP35 proteins may contribute to observed differences in pathogenicity, but these are unlikely to be the major determinant. However, the high level of similarity in structure and the low tolerance for sequence variability, coupled with the multiple critical roles played by Ebola virus VP35 proteins, highlight the viability of VP35 as a potential target for therapeutic development. Structural and functional characterization of Reston Ebola virus VP35 interferon inhibitory domain.,Leung DW, Shabman RS, Farahbakhsh M, Prins KC, Borek DM, Wang T, Muhlberger E, Basler CF, Amarasinghe GK J Mol Biol. 2010 Jun 11;399(3):347-57. Epub 2010 Apr 24. PMID:20399790 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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