Structure of human methionine aminopeptidase-2 complexed with fumagillin
Structure of human methionine aminopeptidase-2 complexed with fumagillin
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DOI：
10.1126/science.282.5392.1324
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发表时间：
1998-11-13
期刊：
影响因子：
56.9
通讯作者：
Clardy, J
中科院分区：
文献类型：
--
作者：
Liu, SP;Widom, J;Clardy, J
真菌代谢产物夫马洁林可抑制新血管形成，一种夫马洁林类似物目前作为抗癌药物正在进行临床试验。夫马洁林的分子靶点是蛋氨酸氨肽酶 - 2（MetAP - 2）。游离的以及受抑制的人MetAP - 2的1.8埃分辨率晶体结构显示，夫马洁林的一个活性环氧基团与MetAP - 2活性位点的组氨酸 - 231之间形成了共价键。夫马洁林与其他部分广泛的疏水作用以及水介导的极性相互作用提供了额外的亲和力。基于夫马洁林的药物可抑制MetAP - 2，但不抑制MetAP - 1，其三维结构也表明了这种特异性的可能决定因素。夫马洁林效力和特异性的结构基础构成了基于结构的药物设计的起点。
The fungal metabolite fumagillin suppresses the formation of new blood vessels, and a fumagillin analog is currently in clinical trials as an anticancer agent. The molecular target of fumagillin is methionine aminopeptidase-2 (MetAP-2). A 1.8 Angstrom resolution crystal structure of free and inhibited human MetAP-2 shows a covalent bond formed between a reactive epoxide of fumagillin and histidine-231 in the active site of MetAP-2. Extensive hydrophobic and water-mediated polar interactions with other parts of fumagillin provide additional affinity. Fumagillin-based drugs inhibit MetAP-2 but not MetAP-1, and the three-dimensional structure also indicates the likely determinants of this specificity. The structural basis for fumagillin's potency and specificity forms the starting point for structure-based drug design.