Title
Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKK<tex>$\beta$</tex>Withaferin A inhibits NF-kappaB activation by targeting cysteine 179 in IKK<tex>$\beta$</tex>
Author
Faculty/Department
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Research group
Proteinchemistry, proteomics and epigenetic signalling(PPES)
Medicinal Chemistry (UAMC)
Publication type
article
Publication
Oxford,
Subject
Pharmacology. Therapy
Source (journal)
Biochemical pharmacology. - Oxford
Volume/pages
91(2014):4, p. 501-509
ISSN
0006-2952
ISI
000342657400009
Carrier
E
Target language
English (eng)
Full text (Publishers DOI)
Affiliation
University of Antwerp
Abstract
The transcription factor NF-kappa B is one of the main players involved in inflammatory responses during which NF-kappa B becomes rapidly activated. However to maintain homeostasis, this NF-kappa B activation profile is only transient. Nevertheless deregulation of NF-kappa B activity is often observed and can lead to chronic inflammatory diseases as well as cancer. Therefore various research projects focus on the development of therapeutics that target the NF-kappa B activation pathway. One such compound is Withaferin A from the Ayurvedic plant Withania somnifera. Several reports already described the NF-kappa B inhibiting, anti-inflammatory capacity of WA, either in vitro as well as in vivo. However the underlying molecular mechanism remains largely unknown. In this paper we demonstrate a direct interaction of WA with the IKK-complex, more specifically with IKK beta, a kinase which is indispensable for the nuclear translocation of NF-kappa B. Hereby WA directly inhibits IKK catalytic activity. By mutation of Cys179 in IKK beta we could demonstrate loss of interaction between IKK beta and WA indicating that WA exerts its anti-inflammatory effects by targeting the crucial Cys179 residue located in the catalytic site of IKK beta. Upon docking of WA to a IKK beta homology structure model, WA was found to fit nicely into the groove of IKK beta where it can form hydrogen bond to stabilize its interaction with Cys179. (C) 2014 Elsevier Inc. All rights reserved.
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