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Sheng-Xue Xie; Wei-Jun Huang; Ze-Qiang Ma; Min Huang; Robert P. Hanzlik; Qi-Zhuang Ye
Acta Crystallographica Section D: Biological Crystallography. 2006;62(4):425-432.
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. © 2006 International Union of Crystallography - all rights reserved.