| Autor: |
Sadek, Jouliana, Wuo, Michael G., Rooklin, David, Hauenstein, Arthur, Hong, Seong Ho, Gautam, Archana, Wu, Hao, Zhang, Yingkai, Cesarman, Ethel, Arora, Paramjit S. |
| Předmět: |
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| Zdroj: |
Nature Communications; 4/14/2020, Vol. 11 Issue 1, p1-14, 14p |
| Abstrakt: |
Protein-protein interactions featuring intricate binding epitopes remain challenging targets for synthetic inhibitors. Interactions of NEMO, a scaffolding protein central to NF-κB signaling, exemplify this challenge. Various regulators are known to interact with different coiled coil regions of NEMO, but the topological complexity of this protein has limited inhibitor design. We undertook a comprehensive effort to block the interaction between vFLIP, a Kaposi's sarcoma herpesviral oncoprotein, and NEMO using small molecule screening and rational design. Our efforts reveal that a tertiary protein structure mimic of NEMO is necessary for potent inhibition. The rationally designed mimic engages vFLIP directly causing complex disruption, protein degradation and suppression of NF-κB signaling in primary effusion lymphoma (PEL). NEMO mimic treatment induces cell death and delays tumor growth in a PEL xenograft model. Our studies with this inhibitor reveal the critical nexus of signaling complex stability in the regulation of NF-κB by a viral oncoprotein. NF-κB signalling involves the scaffold protein NEMO, which can be bound by the oncoprotein vFLIP to promote cell survival and oncogenic transformation. Here the authors rationally engineer a tertiary protein mimic of NEMO to disrupt the vFLIP-NEMO interaction to induce cell death. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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