Unknown

Dataset Information

0

Modulation of virus-induced NF-?B signaling by NEMO coiled coil mimics.


ABSTRACT: Protein-protein interactions featuring intricate binding epitopes remain challenging targets for synthetic inhibitors. Interactions of NEMO, a scaffolding protein central to NF-?B 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-?B 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-?B by a viral oncoprotein.

SUBMITTER: Sadek J 

PROVIDER: S-EPMC7156456 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics.

Sadek Jouliana J   Wuo Michael G MG   Rooklin David D   Hauenstein Arthur A   Hong Seong Ho SH   Gautam Archana A   Wu Hao H   Zhang Yingkai Y   Cesarman Ethel E   Arora Paramjit S PS  

Nature communications 20200414 1


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, a  ...[more]

Similar Datasets

| S-EPMC4302062 | biostudies-literature
| S-EPMC9889916 | biostudies-literature
| S-EPMC3311051 | biostudies-literature
| S-EPMC4523862 | biostudies-literature
| S-EPMC6393490 | biostudies-literature
| S-EPMC7494571 | biostudies-literature
| S-EPMC10245860 | biostudies-literature
| S-EPMC7086394 | biostudies-literature
| S-EPMC7292913 | biostudies-literature
| S-EPMC2760843 | biostudies-literature