Structural analysis of metalloform-selective inhibition of methionine aminopeptidase

Sheng Xue Xie, Wei Jun Huang, Ze Qiang Ma, Min Huang, Robert P. Hanzlik, Qizhuang Ye

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)425-432
Number of pages8
JournalActa Crystallographica Section D: Biological Crystallography
Volume62
Issue number4
DOIs
StatePublished - Apr 2006
Externally publishedYes

Fingerprint

methionine
Aminopeptidases
structural analysis
Structural analysis
Methionine
inhibitors
Metals
Ions
Carboxylic Acids
Metal ions
furans
carboxylic acids
Coordination Complexes
Enzyme Inhibitors
metal ions
selectivity
Antineoplastic Agents
Escherichia coli
Conformations
Crystal structure

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics
  • Condensed Matter Physics
  • Structural Biology

Cite this

Structural analysis of metalloform-selective inhibition of methionine aminopeptidase. / Xie, Sheng Xue; Huang, Wei Jun; Ma, Ze Qiang; Huang, Min; Hanzlik, Robert P.; Ye, Qizhuang.

In: Acta Crystallographica Section D: Biological Crystallography, Vol. 62, No. 4, 04.2006, p. 425-432.

Research output: Contribution to journalArticle

Xie, Sheng Xue ; Huang, Wei Jun ; Ma, Ze Qiang ; Huang, Min ; Hanzlik, Robert P. ; Ye, Qizhuang. / Structural analysis of metalloform-selective inhibition of methionine aminopeptidase. In: Acta Crystallographica Section D: Biological Crystallography. 2006 ; Vol. 62, No. 4. pp. 425-432.
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