Variable active site loop conformations accommodate the binding of macrocyclic largazole analogues to HDAC8.
Variable active site loop conformations accommodate the binding of macrocyclic largazole analogues to HDAC8.
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DOI：
10.1021/acs.biochem.5b00010
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发表时间：
2015-03-31
期刊：
影响因子：
2.9
通讯作者：
Christianson, David W.
中科院分区：
文献类型：
--
作者：
Decroos, Christophe;Clausen, Dane J.;Haines, Brandon E.;Wiest, Olaf;Williams, Robert M.;Christianson, David W.
大环缩酚肽Largazole是金属依赖性组蛋白脱乙酰酶（HDAC）的有效抑制剂，其中一些是癌症化疗的药物靶点。事实上，Largazole部分类似于Romidepsin（FK 228），一种已被批准用于临床的大环缩酚肽。每种抑制剂含有与活性位点Zn 2+离子配位的侧链硫醇，如在HDAC 8-Largazole络合物的X射线晶体结构中观察到的[科尔，K. E.的; Dowling，D. P的; Boone，M.一、菲利普斯，A. J.道：Christianson，D. W. J. Am. 2011，133，12474]。在这里，我们报告的X-射线晶体结构的HDAC 8与三个合成类似物的Largazole，其中缩肽酯被替换为刚性酰胺键。在这些类似物中的两个中，6元吡啶环也被大环骨架中的5元噻唑环取代（具有两个不同的取向）。每种类似物的侧链巯基与活性位点Zn 2+离子配位，具有近乎理想的几何形状，从而保留了拉格唑抑制的标志性结构特征。令人惊讶的是，与Largazole的结合相比，这些类似物在活性位点侧翼的L1和L2环中触发替代构象变化。然而，尽管存在这些结构差异，但抑制效力通常与Largazole的抑制效力相当或仅略低于Largazole的抑制效力。因此，本研究揭示了大环抑制剂与HDAC 8结合的重要的新的结构-亲和力关系。
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 HDAC8–Largazole complex [Cole, K. E.; Dowling, D. P.; Boone, M. A.; Phillips, A. J.; Christianson, D. W. J. Am. Chem. Soc. 2011, 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 6-membered pyridine ring is also substituted (with two different orientations) for the 5-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 the L1 and L2 loops 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.
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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
同基噻唑啉 - 恶唑类似物的合成和HDAC抑制活性。
影响因子：
2.7
作者：
Guerra-Bubb, Jennifer M.;Bowers, Albert A.;Smith, William B.;Paranal, Ronald;Estiu, Guillermina;Wiest, Olaf;Bradner, James E.;Williams, Robert M.
通讯作者：
Williams, Robert M.
影响因子：
4
作者：
Decroos, Christophe;Bowman, Christine M.;Moser, Joe-Ann S.;Christianson, Karen E.;Deardorff, Matthew A.;Christianson, David W.
通讯作者：
Christianson, David W.
影响因子：
5.7
作者：
Delcuve GP;Khan DH;Davie JR
通讯作者：
Davie JR
影响因子：
15
作者：
Kunze MB;Wright DW;Werbeck ND;Kirkpatrick J;Coveney PV;Hansen DF
通讯作者：
Hansen DF