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Science 13 November 1998:
Vol. 282. no. 5392, pp. 1324 - 1327
DOI: 10.1126/science.282.5392.1324
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Reports

Structure of Human Methionine Aminopeptidase-2 Complexed with Fumagillin

Shenping Liu, Joanne Widom, Christopher W. Kemp, Craig M. Crews, Jon Clardy *

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 Å 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.

S. Liu, J. Widom, J. Clardy, Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA. C. W. Kemp, Kemp Biotechnologies, Incorporated, Frederick, MD 21704, USA. C. M. Crews, Department of Molecular, Cellular, and Developmental Biology, Kline Biology Tower, Yale University, New Haven, CT 06520-8103, USA.
*   To whom correspondence should be addressed. E-mail: jcc12{at}cornell.edu

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