STRUCTURE OF HUMAN METHIONINE AMINOPEPTIDASE-2 COMPLEXED WITH FUMAGILLIN

The fungal metabolite fumagillin suppresses the formation of new blood vessels, and a fumagillin analog is currently in clinical trials as a n anticancer agent. The molecular target of fumagillin is methionine a minopeptidase-2 (MetAP-2). A 1.8 Angstrom resolution crystal structure of free and inhibited human MetAP-2 shows a covalent bond formed betw een a reactive epoxide of fumagillin and histidine-231 in the active s ite of MetAP-2. Extensive hydrophobic and water-mediated polar interac tions with other parts of fumagillin provide additional affinity. Fuma gillin-based drugs inhibit MetAP-2 but not MetAP-1, and the three-dime nsional structure also indicates the likely determinants of this speci ficity. The structural basis for fumagillin's potency and specificity forms the starting point for structure-based drug design.