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.