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Structure of Human Methionine Aminopeptidase-2 Complexed with Fumagillin
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 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.
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Metadata
- Authors
- Liu, S., Widom, J., Kemp, C. W., Crews, C. M., & Clardy, J.
- Affiliations
- Cornell University (US)
- Corresponding author
- Clardy, Jon
- Venue
- Science
- Published
- 1998-11-13
- Volume
- 282
- Issue
- 5392
- Pages
- 1324-1327
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2085785716
- Cited by
- 440
- References
- 28
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 14 · 2023: 14 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 13 · 2018: 13 · 2017: 5 · 2016: 10 · 2015: 14 · 2014: 14 · 2013: 16 · 2012: 13
- FWCI
- 13.01
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA024487, CA 59021, R01CA059021, CA-24487)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Peptidase Inhibition and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- methionine aminopeptidase 2, fumagillin, crystal structure, enzyme-inhibitor complex, antivascular agents, anticancer agents, enzyme specificity, structure-based drug design
- MeSH terms
- Amino Acid Sequence, Aminopeptidases, Binding Sites, Cyclohexanes, Fatty Acids, Unsaturated, Humans, Hydrogen Bonding, Metalloendopeptidases, Models, Molecular, Molecular Sequence Data, Protein Conformation, Sesquiterpenes, Sequence Alignment, Protein Structure, Secondary, Crystallography, X-Ray
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