6npp | pdb_00006npp
Crystal structure of Epstein-Barr Virus Nuclear Antigen-1, EBNA1, bound to fragments
Structural highlights
FunctionEBNA1_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.[1] Publication Abstract from PubMedEpstein-Barr virus (EBV) is a DNA tumor virus responsible for 1 to 2% of human cancers including subtypes of Burkitt's lymphoma, Hodgkin's lymphoma, gastric carcinoma, and nasopharyngeal carcinoma (NPC). Persistent latent infection drives EBV-associated tumorigenesis. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated tumors and is therefore an attractive target for therapeutic intervention. It is a multifunctional DNA binding protein critical for viral replication, genome maintenance, viral gene expression, and host cell survival. Using a fragment-based approach and x-ray crystallography, we identify a 2,3-disubstituted benzoic acid series that selectively inhibits the DNA binding activity of EBNA1. We characterize these inhibitors biochemically and in cell-based assays, including chromatin immunoprecipitation and DNA replication assays. In addition, we demonstrate the potency of EBNA1 inhibitors to suppress tumor growth in several EBV-dependent xenograft models, including patient-derived xenografts for NPC. These inhibitors selectively block EBV gene transcription and alter the cellular transforming growth factor-beta (TGF-beta) signaling pathway in NPC tumor xenografts. These EBNA1-specific inhibitors show favorable pharmacological properties and have the potential to be further developed for the treatment of EBV-associated malignancies. Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.,Messick TE, Smith GR, Soldan SS, McDonnell ME, Deakyne JS, Malecka KA, Tolvinski L, van den Heuvel APJ, Gu BW, Cassel JA, Tran DH, Wassermann BR, Zhang Y, Velvadapu V, Zartler ER, Busson P, Reitz AB, Lieberman PM Sci Transl Med. 2019 Mar 6;11(482). pii: 11/482/eaau5612. doi:, 10.1126/scitranslmed.aau5612. PMID:30842315[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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