Variable Active Site Loop Conformations Accommodate the Binding of Macrocyclic Largazole Analogues to HDAC8

被引:51
|
作者
Decroos, Christophe [1 ]
Clausen, Dane J. [2 ]
Haines, Brandon E. [3 ]
Wiest, Olaf [3 ,4 ]
Williams, Robert M. [2 ,5 ]
Christianson, David W. [1 ]
机构
[1] Univ Penn, Dept Chem, Roy & Diana Vagelos Labs, Philadelphia, PA 19104 USA
[2] Colorado State Univ, Dept Chem, Ft Collins, CO 80523 USA
[3] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
[4] Peking Univ, Shenzhen Grad Sch, Lab Chem Genom, Lab Computat Chem & Drug Design, Shenzhen 518055, Peoples R China
[5] Univ Colorado, Ctr Canc, Aurora, CO 80045 USA
基金
美国国家卫生研究院;
关键词
HISTONE DEACETYLASE INHIBITOR; CATALYTIC-ACTIVITY; CRYSTAL-STRUCTURE; DEPSIPEPTIDE; VORINOSTAT; MECHANISM; SUBSTRATE; ROLES; FK228;
D O I
10.1021/acs.biochem.5b00010
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The macrocyclic depsipeptide Largazole is a potent inhibitor of metal-dependent histone deacetylases (HDACs), some of which are drug targets for cancer chemotherapy. Indeed, Largazole partially resembles Romidepsin (FK228), a macrocyclic depsipeptide already approved for clinical use. Each inhibitor contains a pendant side chain thiol that coordinates to the active site Zn2+ ion, as observed in the X-ray crystal structure of the HDAC8Largazole complex [Cole, K. E., Dowling, D. P., Boone, M. A., Phillips, A. J., and Christianson, D. W. (2011) J. Am. Chem. Soc. 133, 12474]. Here, we report the X-ray crystal structures of HDAC8 complexed with three synthetic analogues of Largazole in which the depsipeptide ester is replaced with a rigid amide linkage. In two of these analogues, a six-membered pyridine ring is also substituted (with two different orientations) for the five-membered thiazole ring in the macrocycle skeleton. The side chain thiol group of each analogue coordinates to the active site Zn2+ ion with nearly ideal geometry, thereby preserving the hallmark structural feature of inhibition by Largazole. Surprisingly, in comparison with the binding of Largazole, these analogues trigger alternative conformational changes in loops L1 and L2 flanking the active site. However, despite these structural differences, inhibitory potency is generally comparable to, or just moderately less than, the inhibitory potency of Largazole. Thus, this study reveals important new structure-affinity relationships for the binding of macrocyclic inhibitors to HDAC8.
引用
收藏
页码:2126 / 2135
页数:10
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