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Structure of human methionine aminopeptidase-2 complexed with fumagillin
1J. Clardy, Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, NY 14853-1301, USA.
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.
Insights
Fumagillin, an anticancer drug candidate, targets methionine aminopeptidase-2 (MetAP-2) by forming a covalent bond. Structural analysis reveals key interactions for drug design and specificity against MetAP-2.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Fumagillin, a fungal metabolite, inhibits angiogenesis and is a potential anticancer agent.
- Its molecular target is methionine aminopeptidase-2 (MetAP-2).
Purpose of the Study:
- To elucidate the structural basis of fumagillin's inhibition of MetAP-2.
- To understand the specificity of fumagillin for MetAP-2 over MetAP-1.
Main Methods:
- X-ray crystallography at 1.8 A resolution.
- Analysis of free and inhibited human MetAP-2 structures.
Main Results:
- A covalent bond is formed between fumagillin's epoxide and histidine-231 in MetAP-2's active site.
- Hydrophobic and water-mediated interactions contribute to binding affinity.
- Structural determinants for MetAP-2 specificity over MetAP-1 were identified.
Conclusions:
- The crystal structure provides a detailed understanding of fumagillin-MetAP-2 interactions.
- This structural information is crucial for structure-based design of novel fumagillin analogs.