Targeting the lateral interactions of transmembrane domain 5 of Epstein-Barr virus latent membrane protein 1 |
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Authors: | Wang Xiaohui Saludes Jonel P Zhao Tina X Csakai Adam Fiorini Zeno Chavez Sherry A Li Jing Lee Gui-In Varga Krisztina Yin Hang |
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Institution: | Department of Chemistry and Biochemistry and Biofrontiers Institute, University of Colorado at Boulder, Boulder, CO 80309-0596, USA. |
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Abstract: | The lateral transmembrane protein-protein interaction has been regarded as "undruggable" despite its importance in many biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) is critical for the constitutive oncogenic activation of the Epstein-Barr virus (EBV). Herein, we report a small molecule agent, NSC 259242 (compound 1), to be a TMD-5 self-association disruptor. Both the positively charged acetimidamide functional groups and the stilbene backbone of compound 1 are essential for its inhibitory activity. Furthermore, cell-based assays revealed that compound 1 inhibits full-length LMP-1 signaling in EBV infected B cells. These studies demonstrated a new strategy for identifying small molecule disruptors for investigating transmembrane protein-protein interactions. |
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