title: Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases.
abstract: Largazole is a macrocyclic depsipeptide originally isolated from the marine cyanobacterium Symploca sp., which is indigenous to the warm, blue-green waters of Key Largo, Florida (whence largazole derives its name). Largazole contains an unusual thiazoline-thiazole ring system that rigidifies its macrocyclic skeleton, and it also contains a lipophilic thioester side chain. Hydrolysis of the thioester in vivo yields largazole thiol, which exhibits remarkable antiproliferative effects and is believed to be the most potent inhibitor of the metal-dependent histone deacetylases (HDACs). Here, the 2.14 Å-resolution crystal structure of the HDAC8-largazole thiol complex is the first of an HDAC complexed with a macrocyclic inhibitor and reveals that ideal thiolate-zinc coordination geometry is the key chemical feature responsible for its exceptional affinity and biological activity. Notably, the core structure of largazole is conserved in romidepsin, a depsipeptide natural product formulated as the drug Istodax recently approved for cancer chemotherapy. Accordingly, the structure of the HDAC8-largazole thiol complex is the first to illustrate the mode of action of a new class of therapeutically important HDAC inhibitors.
authors.affiliation: Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Cole
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Dowling
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Boone
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Phillips
authors.forename: David W
authors.initials: DW
authors.lastname: Christianson
mesh_terms: D018360:Crystallography, X-Ray; D000458:Cyanobacteria / Q000737:chemistry; D047630:Depsipeptides / Q000737:chemistry* / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D013844:Thiazoles; C527895:largazole; C409470:HDAC8 protein, human; D006655:Histone Deacetylases