A systematic protocol for the characterization of Hsp90 modulators.
Several Hsp90 modulators have been identified including the N-terminal ligand geldanamycin (GDA), the C-terminal ligand novobiocin (NB), and the co-chaperone disruptor celastrol. Other Hsp90 modulators elicit a mechanism of action that remains unknown. For example, the natural product gedunin and the synthetic anti-spermatogenic agent H2-gamendazole, recently identified Hsp90 modulators, manifest biological activity through undefined mechanisms. Herein, we report a series of biochemical techniques used to classify such modulators into identifiable categories. Such studies provided evidence that gedunin and H2-gamendazole both modulate Hsp90 via a mechanism similar to celastrol, and unlike NB or GDA.
Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, United States.
Robert L
RL
Matts
Gary E L
GE
Brandt
Yuanming
Y
Lu
Anshuman
A
Dixit
Mehdi
M
Mollapour
Suiquan
S
Wang
Alison C
AC
Donnelly
Leonard
L
Neckers
Gennady
G
Verkhivker
Brian S J
BS
Blagg
D016227:Benzoquinones / Q000494:pharmacology; D045744:Cell Line, Tumor; D002846:Chromatography, Affinity; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008958:Models, Molecular; D009675:Novobiocin / Q000494:pharmacology; D053978:Pentacyclic Triterpenes; D014315:Triterpenes / Q000494:pharmacology
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; D009675:Novobiocin; C050414:celastrol; C001277:geldanamycin