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    Structural analysis of metalloform-selective inhibition of methionine aminopeptidase

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    ActaCrystal_hanzlik.pdf (910.7Kb)
    Issue Date
    2006-04
    Author
    Xie, Sheng-Xue
    Huang, Wei-Jun
    Ma, Ze-Qiang
    Huang, Min
    Hanzlik, Robert P.
    Ye, Qi-Zhuang
    Publisher
    International Union of Crystallography
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    One of the challenges in the development of methionine aminopeptidase (MetAP) inhibitors as antibacterial and anticancer agents is to define the metal ion actually used by MetAP in vivo and to discover MetAP inhibitors that can inhibit the metalloform that is relevant in vivo. Two distinct classes of novel nonpeptidic MetAP inhibitors that are not only potent but also highly selective for either the MnII or CoII form have been identified. Three crystal structures of Escherichia coli MetAP complexed with the metalloform-selective inhibitors 5-(2,5-dichlorophenyl)furan-2-carboxylic acid (2), 5-[2-(trifluoromethyl)phenyl]furan-2-carboxylic acid (3) and N-cyclopentyl-N-(thiazol-2-yl)oxalamide (4) have been solved and analysis of these structures has revealed the structural basis for their metalloform-selective inhibition. The MnII-form selective inhibitors (2) and (3) both use their carboxylate group to coordinate with the two MnII ions at the dinuclear metal site and both adopt a non-coplanar conformation for the two aromatic rings. The unique coordination geometry of these inhibitors may determine their MnII-form selectivity. In contrast, the CoII-form selective inhibitor (4) recruits an unexpected third metal ion, forming a trimetallic enzyme–metal–inhibitor complex. Thus, an important factor in the selectivity of (4) for the CoII form may be a consequence of a greater preference for a softer N,O-donor ligand for the softer CoII.
    URI
    http://hdl.handle.net/1808/8314
    DOI
    https://doi.org/10.1107/S0907444906003878
    Collections
    • Distinguished Professors Scholarly Works [918]
    • Medicinal Chemistry Scholarly Works [244]
    Citation
    Xie SX, Huang WJ, Ma ZQ, Huang M, Hanzlik RP, Ye QZ, "Structural analysis of metalloform-selective inhibition of methionine aminopeptidase." Acta Cryst., D62, 425-432 (2006). PMID: 16552144 http://dx.doi.org/10.1107/S0907444906003878

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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