Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors.
Diverse modes of binding in structures of Leishmania major N-myristoyltransferase with selective inhibitors.
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DOI：
10.1107/s2052252514013001
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发表时间：
2014-07-01
期刊：
影响因子：
3.9
通讯作者：
Wilkinson AJ
中科院分区：
文献类型：
--
作者：
Brannigan JA;Roberts SM;Bell AS;Hutton JA;Hodgkinson MR;Tate EW;Leatherbarrow RJ;Smith DF;Wilkinson AJ
具有四种不同利什曼病选择性小分子抑制剂的N-肉豆蔻酰转移酶的晶体结构确定了关键的结合位点残基，并提出了设计具有更高亲和力的化合物的策略。利什曼病是一系列与免疫功能障碍有关的全球性贫困疾病，是高发病率的原因。尽管这些疾病的历史很长，但没有有效的疫苗，目前使用的药物因疗效中等、副作用复杂和出现耐药性而受到各种影响。因此，人们普遍认为需要新的治疗方法。N-肉豆蔻酰转移酶（NMT）已在临床前被验证为治疗真菌和寄生虫感染的靶标。在先前报道的高通量筛选程序中，已经鉴定了许多具有抗杜氏利什曼原虫NMT活性的命中化合物。在这里，高分辨率晶体结构的代表性化合物，从四个击中系列的三元复合物与肉豆蔻酰辅酶A和NMT从密切相关的L。主要报道。结构表明，抑制剂与肽结合沟在一个位点附近的结合肉豆蔻酰辅酶A和催化α-羧酸的Leu 421。每种抑制剂与蛋白质进行广泛的非极性接触以及少量的极性接触。值得注意的是，这些化合物利用了肽结合沟的不同特征，并共同占据了这个口袋的相当大的体积，这表明有可能设计具有显着增强结合的嵌合抑制剂。尽管寄生虫和人类NMT的活性位点高度保守，但抑制剂选择性地作用于宿主酶。的构象灵活性在侧链中的Tyr 217在赋予选择性的作用进行了讨论。
Crystal structures of N-myristoyltransferase with four distinct Leishmania-selective small-molecule inhibitors identify key binding-site residues and suggest strategies to design compounds with increased affinity. The leishmaniases are a spectrum of global diseases of poverty associated with immune dysfunction and are the cause of high morbidity. Despite the long history of these diseases, no effective vaccine is available and the currently used drugs are variously compromised by moderate efficacy, complex side effects and the emergence of resistance. It is therefore widely accepted that new therapies are needed. N-Myristoyltransferase (NMT) has been validated pre-clinically as a target for the treatment of fungal and parasitic infections. In a previously reported high-throughput screening program, a number of hit compounds with activity against NMT from Leishmania donovani have been identified. Here, high-resolution crystal structures of representative compounds from four hit series in ternary complexes with myristoyl-CoA and NMT from the closely related L. major are reported. The structures reveal that the inhibitors associate with the peptide-binding groove at a site adjacent to the bound myristoyl-CoA and the catalytic α-carboxylate of Leu421. Each inhibitor makes extensive apolar contacts as well as a small number of polar contacts with the protein. Remarkably, the compounds exploit different features of the peptide-binding groove and collectively occupy a substantial volume of this pocket, suggesting that there is potential for the design of chimaeric inhibitors with significantly enhanced binding. Despite the high conservation of the active sites of the parasite and human NMTs, the inhibitors act selectively over the host enzyme. The role of conformational flexibility in the side chain of Tyr217 in conferring selectivity is discussed.