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Structural analysis of metalloform-selective inhibition of methionine aminopeptidase.
- Source :
-
Acta crystallographica. Section D, Biological crystallography [Acta Crystallogr D Biol Crystallogr] 2006 Apr; Vol. 62 (Pt 4), pp. 425-32. Date of Electronic Publication: 2006 Mar 18. - Publication Year :
- 2006
-
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 Mn(II) or Co(II) 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 Mn(II)-form selective inhibitors (2) and (3) both use their carboxylate group to coordinate with the two Mn(II) 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 Mn(II)-form selectivity. In contrast, the Co(II)-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 Co(II) form may be a consequence of a greater preference for a softer N,O-donor ligand for the softer Co(II).
- Subjects :
- Aminopeptidases antagonists & inhibitors
Aminopeptidases metabolism
Binding Sites
Cobalt chemistry
Crystallization
Crystallography, X-Ray
Heterocyclic Compounds, 2-Ring chemistry
Heterocyclic Compounds, 2-Ring metabolism
Manganese chemistry
Methionyl Aminopeptidases
Molecular Structure
Protease Inhibitors metabolism
Protease Inhibitors pharmacology
Protein Binding
Protein Structure, Tertiary
Aminopeptidases chemistry
Escherichia coli enzymology
Metals chemistry
Protease Inhibitors chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 0907-4449
- Volume :
- 62
- Issue :
- Pt 4
- Database :
- MEDLINE
- Journal :
- Acta crystallographica. Section D, Biological crystallography
- Publication Type :
- Academic Journal
- Accession number :
- 16552144
- Full Text :
- https://doi.org/10.1107/S0907444906003878