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Structure of human methionine aminopeptidase-2 complexed with fumagillin.

Author(s): Stephanie S. Liu, Frederick Kemp, J Clardy, Deidra C Crews, J Widom

Publication date: 1998-11-13

Keywords: Amino Acid Sequence, Aminopeptidases, antagonists & inhibitors, chemistry, metabolism, Binding Sites, Crystallography, X-Ray, Cyclohexanes, Fatty Acids, Unsaturated, pharmacology, Humans, Hydrogen Bonding, Metalloendopeptidases, Models, Molecular, Molecular Sequence Data, Protein Conformation, Protein Structure, Secondary, Sequence Alignment, Sesquiterpenes

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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.

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PubMed ID:: 9812898

DOI:: 10.1126/science.282.5392.1324

ScienceOpen disciplines: Chemistry

Keywords: Amino Acid Sequence,Aminopeptidases,antagonists & inhibitors,chemistry,metabolism,Binding Sites,Crystallography, X-Ray,Cyclohexanes,Fatty Acids, Unsaturated,pharmacology,Humans,Hydrogen Bonding,Metalloendopeptidases,Models, Molecular,Molecular Sequence Data,Protein Conformation,Protein Structure, Secondary,Sequence Alignment,Sesquiterpenes

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