Inhibition of monometalated methionine aminopeptidase: Inhibitor discovery and crystallographic analysis

Min Huang, Sheng Xue Xie, Ze Qiang Ma, Qing Qing Huang, Fa Jun Nan, Qi Zhuang Ye

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Two divalent metal ions are commonly seen in the active-site cavity of methionine aminopeptidase, and at least one of the metal ions is directly involved in catalysis. Although ample structural and functional information is available for dimetalated enzyme, methionine aminopeptidase likely functions as a monometalated enzyme under physiological conditions. Information on structure, as well as catalysis and inhibition, of the monometalated enzyme is lacking. By improving conditions of high-throughput screening, we identified a unique inhibitor with specificity toward the monometalated enzyme. Kinetic characterization indicates a mutual exclusivity in binding between the inhibitor and the second metal ion at the active site. This is confirmed by X-ray structure, and this inhibitor coordinates with the first metal ion and occupies the space normally occupied by the second metal ion. Kinetic and structural analyses of the inhibition by this and other inhibitors provide insight in designing effective inhibitors of methionine aminopeptidase.

Original languageEnglish (US)
Pages (from-to)5735-5742
Number of pages8
JournalJournal of Medicinal Chemistry
Volume50
Issue number23
DOIs
StatePublished - Nov 15 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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