6NPM

Crystal structure of Epstein-Barr Virus Nuclear Antigen-1, EBNA1, bound to fragments

Summary for 6NPM

• Entry DOI: 10.2210/pdb6npm/pdb
• Related: 6NPI
• Descriptor: Epstein-Barr nuclear antigen 1, 5-(phenylethynyl)pyridine-3-carboxylic acid (3 entities in total)
• Functional Keywords: ebna1, dna binding protein, epstein-barr virus, viral protein, viral protein-inhibitor complex, viral protein/inhibitor
• Biological source: Epstein-Barr virus (strain B95-8) (HHV-4)
• Total number of polymer chains: 2
• Total formula weight: 30836.58

Authors

Messick, T.E. (deposition date: 2019-01-17, release date: 2019-03-20, Last modification date: 2023-10-11)

Primary citation

Messick, T.E.,Smith, G.R.,Soldan, S.S.,McDonnell, M.E.,Deakyne, J.S.,Malecka, K.A.,Tolvinski, L.,van den Heuvel, A.P.J.,Gu, B.W.,Cassel, J.A.,Tran, D.H.,Wassermann, B.R.,Zhang, Y.,Velvadapu, V.,Zartler, E.R.,Busson, P.,Reitz, A.B.,Lieberman, P.M.
Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth.
Sci Transl Med, 11:-, 2019

PubMed Abstract: Epstein-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-β (TGF-β) 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.

PubMed: 30842315
DOI: 10.1126/scitranslmed.aau5612

Experimental method

X-RAY DIFFRACTION (1.603 Å)