title: Inhibition of transcription factor NF-kappaB by sesquiterpene lactones: a proposed molecular mechanism of action.
abstract: Many sesquiterpene lactones (SLs) possess considerable anti-inflammatory activity. They inhibit the transcription factor NF-kappaB by selectively alkylating its p65 subunit probably by reacting with cysteine residues. Here we assayed 28 sesquiterpene lactones for their ability to inhibit NF-kappaB. The majority of the potent NF-kappaB inhibitors possess two reactive centers in form of an alpha-methylene-gamma-lactone group and an alpha,beta- or alpha,beta,gamma,delta-unsaturated carbonyl group. Based on computer molecular modelling we propose a molecular mechanism of action, which is able to explain the p65 selectivity of the SLs and the observed correlation of high activity with alkylant bifunctionality. A single bifunctional SL molecule can alkylate the cysteine residue (Cys 38) in the DNA binding loop 1 (L1) and a further cysteine (Cys 120) in the nearby E' region. This cross link alters the position of tyrosine 36 and additional amino acids in such a way that their specific interactions with the DNA become impossible. We also created a model for monofunctional SLs.
authors.affiliation: Institut für Pharmazeutische Biologie, Universität Freiburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Rüngeler
authors.forename: V
authors.initials: V
authors.lastname: Castro
authors.forename: G
authors.initials: G
authors.lastname: Mora
authors.forename: N
authors.initials: N
authors.lastname: Gören
authors.forename: W
authors.initials: W
authors.lastname: Vichnewski
authors.forename: H L
authors.initials: HL
authors.lastname: Pahl
authors.forename: I
authors.initials: I
authors.lastname: Merfort
authors.forename: T J
authors.initials: TJ
authors.lastname: Schmidt
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D007783:Lactones / Q000494:pharmacology*; D008958:Models, Molecular; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010936:Plant Extracts / Q000494:pharmacology; D012717:Sesquiterpenes / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D007783:Lactones; D016328:NF-kappa B; D010936:Plant Extracts; D012717:Sesquiterpenes