A novel allosteric mechanism of NF-κB dimerization and DNA binding targeted by an anti-inflammatory drug

Shaked Ashkenazi, Alexander Plotnikov, Anat Bahat, Efrat Ben-Zeev, Shira Warszawski, Rivka Dikstein

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

The NF-κB family plays key roles in immune and stress responses, and its deregulation contributes to several diseases. Therefore its modulation has become an important therapeutic target. Here, we used a high-throughput screen for small molecules that directly inhibit dimerization of the NF-κB protein p65. One of the identified inhibitors is withaferin A (WFA), a documented anticancer and anti-inflammatory compound. Computational modeling suggests that WFA contacts the dimerization interface on one subunit and surface residues E285 and Q287 on the other. Despite their locations far from the dimerization site, E285 and Q287 substitutions diminished both dimerization and the WFA effect. Further investigation revealed that their effects on dimerization are associated with their proximity to a conserved hydrophobic core domain (HCD) that is crucial for dimerization and DNA binding. Our findings established NF-κB dimerization as a drug target and uncovered an allosteric domain as a target of WFA action.

Original languageEnglish
Pages (from-to)1237-1247
Number of pages11
JournalMolecular and Cellular Biology
Volume36
Issue number8
DOIs
StatePublished - 2016
Externally publishedYes

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