Computational and conformational evaluation of FTase alternative substrates: insight into a novel enzyme binding pocket.
Computational and conformational evaluation of FTase alternative substrates: insight into a novel enzyme binding pocket.
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FTase 替代底物的计算和构象评估：深入了解新型酶结合袋。
DOI：
10.1021/ci0496550
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发表时间：
2005
影响因子：
5.6
通讯作者：
Gibbs,RichardA
中科院分区：
文献类型：
--
作者：
Henriksen,BrianS;Zahn,ToddJ;Evanseck,JeffreyD;Firestine,StevenM;Gibbs,RichardA
蛋白法尼基转移酶（FTase）是重要的抗癌药物靶点。在开发基于类异戊二烯二磷酸盐的FTase抑制剂的努力中，已经观察到保守修饰的类似物与酶结合的能力发生了惊人的变化。例如，2Z-GGPP是具有高结合亲和力的替代底物，而GGPP不是替代底物。利用高分辨率FTase晶体结构的可用性，我们利用药效团和对接研究阐明了类异戊二烯类似物的新结合袋。2Z-GGPP的前两个异戊二烯单元之间的独特构象允许2Z-GGPP利用这个新的结合袋，而不是GGPP。发现的构象允许分子采用反应构象，同时将疏水基团置于主要疏水的结合口袋内。对13c标记的2z -法尼醇的核磁共振研究支持了这一计算结果，证实了计算预测的构象在溶液中也是有利的。这些发现表明，配体构象灵活性可能是开发FTase抑制剂和替代底物的重要设计考虑因素。
Protein farnesyltransferase (FTase) is an important anticancer drug target. In an effort to develop isoprenoid diphosphate-based FTase inhibitors, striking variations have been observed in the ability of conservatively modified analogues to bind to the enzyme. For example, 2Z-GGPP is an alternative substrate with high binding affinity, while GGPP is not an alternative substrate. Using the availability of high-resolution FTase crystal structures, we have used pharmacophore and docking studies to elucidate a new binding pocket for isoprenoid analogues. The unique conformations between the first two isoprene units of 2Z-GGPP, but not GGPP, allows 2Z-GGPP to exploit this new binding pocket. The discovered conformation allows the molecule to adopt a reactive conformation while placing hydrophobic groups within the predominately hydrophobic binding pocket. This computational finding is supported by NMR studies on13C-labeled 2Z-farnesol, which confirm that the computationally predicted conformation is also favored in solution. These discoveries suggest that ligand conformational flexibility may be an important design consideration for the development of both inhibitors and alternative substrates of FTase.