Cited by 455Enzyme Structure and FunctionPeptidase Inhibition and AnalysisAmino Acid Enzymes and Metabolism

Structure of Human Methionine Aminopeptidase-2 Complexed with Fumagillin

Liu, Shenping, Widom, Joanne, Kemp, Christopher W., Crews, Craig M., Clardy, Jon·1998·Science

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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Crossref · 10.1126/science.282.5392.1324

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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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