Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.
Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.
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DOI：
10.1016/j.chembiol.2009.01.014
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发表时间：
2009-02-27
影响因子：
--
通讯作者：
Beese LS
中科院分区：
文献类型：
--
作者：
Hast MA;Fletcher S;Cummings CG;Pusateri EE;Blaskovich MA;Rivas K;Gelb MH;Van Voorhis WC;Sebti SM;Hamilton AD;Beese LS
蛋白法尼基转移酶（FTase）催化细胞内信号转导网络中60多种蛋白质的翻译后脂质修饰。FTase抑制剂已成为开发抗癌治疗剂的重要靶标，并且最近已成为治疗由原生动物病原体引起的寄生虫病（包括疟疾（恶性疟原虫））的重要靶标。我们提出了哺乳动物FTase与基于乙二胺支架的五种抑制剂的复合物的X射线晶体学结构，其中两种表现出对恶性疟原虫FTase超过1000倍的选择性抑制。这些结构揭示了抑制剂和酶中控制结合和选择性的主要决定因素。与构建的恶性疟原虫FTase同源模型的比较表明，有机会进一步提高新一代抗疟抑制剂的选择性。
Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.
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DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.9
作者：
Dolence, JM;Cassidy, PB;Poulter, CD
通讯作者：
Poulter, CD
影响因子：
2.9
作者：
Long, SB;Casey, PJ;Beese, LS
通讯作者：
Beese, LS
DOI：
10.1073/pnas.241407898
发表时间：
2001-11-06
影响因子：
11.1
作者：
Long, SB;Hancock, PJ;Beese, LS
通讯作者：
Beese, LS
影响因子：
2.9
作者：
Hightower, KE;Huang, CC;Fierke, CA
通讯作者：
Fierke, CA