期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 133, 期 32, 页码 12474-12477出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja205972n
关键词
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资金
- Office of Biological and Environmental Research of the US Department of Energy
- Office of Basic Energy Sciences of the US Department of Energy
- National Center for Research Resources of the National Institutes of Health [P41RR012408]
- National Institutes of Health [GM49758, CA110246]
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 thio ester 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 angstrom-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.
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