title: Omuralide and vibralactone: differences in the proteasome- β-lactone-γ-lactam binding scaffold alter target preferences.
abstract: Despite their structural similarity, the natural products omuralide and vibralactone have different biological targets. While omuralide blocks the chymotryptic activity of the proteasome with an IC50 value of 47 nM, vibralactone does not have any effect at this protease up to a concentration of 1 mM. Activity-based protein profiling in HeLa cells revealed that the major targets of vibralactone are APT1 and APT2.
authors.affiliation: Center for Integrated Protein Science Munich, Department Chemie, Technische Universität München, Lichtenbergstrasse 4, 85747 Garching (Germany).
authors.forename: Anja
authors.initials: A
authors.lastname: List
authors.forename: Evelyn
authors.initials: E
authors.lastname: Zeiler
authors.forename: Nerea
authors.initials: N
authors.lastname: Gallastegui
authors.forename: Marion
authors.initials: M
authors.lastname: Rusch
authors.forename: Christian
authors.initials: C
authors.lastname: Hedberg
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Sieber
authors.forename: Michael
authors.initials: M
authors.lastname: Groll
mesh_terms: D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000494:pharmacology; D007783:Lactones / Q000737:chemistry* / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D021122:Protein Subunits; D013329:Structure-Activity Relationship; D013869:Thiolester Hydrolases / Q000037:antagonists & inhibitors*
chemical_list: D007769:Lactams; D007783:Lactones; D061988:Proteasome Inhibitors; D021122:Protein Subunits; C117645:omuralide; C522315:vibralactone; C402226:LYPLA1 protein, human; C581317:LYPLA2 protein, human; D013869:Thiolester Hydrolases
keywords: click chemistry; drug development; natural products; proteasome; protein crystallography