Liu S, Widom J, Kemp C W, Crews C M, Clardy J
J. Clardy, Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA.
Science. 1998 Nov 13;282(5392):1324-7. doi: 10.1126/science.282.5392.1324.
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 A 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.
真菌代谢产物烟曲霉素可抑制新血管的形成，一种烟曲霉素类似物目前正作为抗癌药物进行临床试验。烟曲霉素的分子靶点是蛋氨酸氨肽酶-2（MetAP-2）。游离和受抑制的人MetAP-2的1.8埃分辨率晶体结构显示，烟曲霉素的一个反应性环氧化物与MetAP-2活性位点中的组氨酸-231之间形成了共价键。与烟曲霉素其他部分广泛的疏水和水介导的极性相互作用提供了额外的亲和力。基于烟曲霉素的药物抑制MetAP-2而不抑制MetAP-1，三维结构也表明了这种特异性的可能决定因素。烟曲霉素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。
