Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases.
Structural basis of the antiproliferative activity of largazole, a depsipeptide inhibitor of the histone deacetylases.
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DOI：
10.1021/ja205972n
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发表时间：
2011-08-17
影响因子：
15
通讯作者：
Christianson, David W.
中科院分区：
文献类型：
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作者：
Cole, Kathryn E.;Dowling, Daniel P.;Boone, Matthew A.;Phillips, Andrew J.;Christianson, David W.
Largazole是一种大环沉积肽，最初从海洋蓝藻细菌Symploca sp.中分离出来，该细菌原产于佛罗里达州Key Largo的温暖蓝绿色水域（Largazole的名字由此而来）。Largazole含有一个不寻常的噻唑-噻唑环系统，使其大环骨架硬化，它还含有亲脂性硫酯侧链。硫酯在体内水解产生大硫唑硫醇，它具有显著的抗增殖作用，被认为是金属依赖性组蛋白去乙酰化酶（HDACs）最有效的抑制剂。在这里，hdac8 -大硫唑硫醇配合物的2.14 Å-resolution晶体结构是HDAC与大环抑制剂配合的第一个晶体结构，并揭示了理想的硫酸锌配位几何结构是其特殊亲和力和生物活性的关键化学特征。值得注意的是，largazole的核心结构在罗米地辛中是保守的，罗米地辛是一种沉淀肽天然产物，最近被批准用于癌症化疗的药物Istodax®。因此，hdac8 -大硫唑硫醇复合物的结构首次说明了一类新的治疗上重要的HDAC抑制剂的作用模式。
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.
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影响因子：
5.2
作者：
Bowers AA;West N;Newkirk TL;Troutman-Youngman AE;Schreiber SL;Wiest O;Bradner JE;Williams RM
通讯作者：
Williams RM
影响因子：
2.9
作者：
CHAKRABARTI, P
通讯作者：
CHAKRABARTI, P
影响因子：
15
作者：
Taori, Kanchan;Paul, Valerie J.;Luesch, Hendrik
通讯作者：
Luesch, Hendrik
影响因子：
5.6
作者：
Gregoretti, IV;Lee, YM;Goodson, HV
通讯作者：
Goodson, HV
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
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作者：
通讯作者：
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