title: A Novel Allosteric Mechanism of NF-κB Dimerization and DNA Binding Targeted by an Anti-Inflammatory Drug.
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.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shaked
authors.initials: S
authors.lastname: Ashkenazi
authors.affiliation: The Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Plotnikov
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Bahat
authors.affiliation: The Nancy and Stephen Grand Israel National Center for Personalized Medicine, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Efrat
authors.initials: E
authors.lastname: Ben-Zeev
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Warszawski
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot, Israel rivka.dikstein@weizmann.ac.il.
authors.forename: Rivka
authors.initials: R
authors.lastname: Dikstein
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000595:Amino Acid Sequence; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects*; D016415:Sequence Alignment; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054358:Withanolides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D051996:Transcription Factor RelA; D054358:Withanolides; D004247:DNA; C009684:withaferin A
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