6pw2

Structural Basis for Cooperative Binding of EBNA1 to the Epstein-Barr Virus Dyad Symmetry Minimal Origin of Replication

spinqualitylabelsall models 6pw2, resolution 3.01Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6pw2 is a 12 chain structure with sequence from Human herpesvirus 4 strain B95-8. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.01Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function EBNA1_EBVB9 Plays an essential role in replication and partitioning of viral genomic DNA during latent viral infection. During this phase, the circular double-stranded viral DNA undergoes replication once per cell cycle and is efficiently partitioned to the daughter cells. EBNA1 activates the initiation of viral DNA replication through binding to specific sites in the viral latent origin of replication, oriP. Additionally, it governs the segregation of viral episomes by mediating their attachment to host cell metaphase chromosomes. Also activates the transcription of several viral latency genes. Finally, it can counteract the stabilization of host p53/TP53 by host USP7, thereby decreasing apoptosis and increasing host cell survival. Publication Abstract from PubMed Epstein-Barr virus is associated with several human malignancies including nasopharyngeal carcinoma, gastric cancer and lymphoma. Latently infected cells carry a circularized EBV episome where the origin of replication (OriP) is comprised of two elements: the family of repeats (FR) and dyad symmetry (DS). The viral protein Epstein-Barr Nuclear Antigen-1 (EBNA1) binds to FR and DS to promote EBV episome maintenance and DNA replication during latent infection in proliferating cells. EBNA1 binding to the DS constitutes a minimal origin of DNA replication. Here, we report the crystal structure of two EBNA1 DNA-binding domain dimers bound to a DS half site. This structure shows that the DNA is smoothly bent allowing for stabilizing interactions between the dimers. The dimer-dimer interface requires an intricate hydrogen bonding network involving residues R491 and D581. When this interface is disrupted, we note loss of stable dimer-dimer complex formation on the DNA, compromised OriP-containing plasmid replication in cells and impaired recruitment of the MCM3 complex to the OriP Surface conservation analysis reveals that these residues are part of a larger conserved surface that may be critical for recruitment of replication machinery to the OriP Our results reveal a new region of EBNA1 critical for its activity and one that may be exploited by targeted small molecules to treat EBV-associated disease.IMPORTANCEEpstein-Barr Virus (EBV) is a causative agent of various malignancies and may also contribute to autoimmune disease. The latent and episomal form of the virus is known to drive EBV-associated oncogenesis. Persistence of the viral episome in proliferating tumor cells requires the interaction of the Epstein-Barr Virus Nuclear Antigen 1 (EBNA1) with the viral origin of plasmid replication OriP. The Dyad Symmetry (DS) element in OriP is the essential minimal replicator of OriP. Here, we report the X-ray crystal structure of EBNA1 bound to DS. The structure reveals a previous unrecognized interface formed between dimers of EBNA1 necessary for cooperative DNA-binding, recruitment of cellular replication machinery, and replication function. These findings provide new insights into the mechanism of EBNA1 function at the replication origin and new opportunities to inhibit EBV latent infection and pathogenesis. Structural Basis for Cooperative Binding of EBNA1 to the Epstein-Barr Virus Dyad Symmetry Minimal Origin of Replication.,Malecka KA, Dheekollu J, Deakyne JS, Wiedmer A, Ramirez UD, Lieberman PM, Messick TE J Virol. 2019 May 29. pii: JVI.00487-19. doi: 10.1128/JVI.00487-19. PMID:31142669 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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