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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These nucleophilic centers are also present in DNA and other biologically relevant compounds, such as glutathione.
“These nucleophilic centers are also present in DNA and other biologically relevant compounds, such as glutathione.116–121”
From Connecting metabolome and phenotype: recent advances in functional metabolomics tools for the identification of bioactive natural products (2024) · cites this paper as [118]
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- 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
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Health Sciences › Medicine › Oncology › 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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