Structure of human methionine aminopeptidase-2 complexed with fumagillin.
Article Details
- CitationCopy to clipboard
Liu S, Widom J, Kemp CW, Crews CM, Clardy J
Structure of human methionine aminopeptidase-2 complexed with fumagillin.
Science. 1998 Nov 13;282(5392):1324-7.
- PubMed ID
- 9812898 [ View in PubMed]
- Abstract
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.