2evm
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crystal structure of methionine aminopeptidase in complex with 5-(2,5-dichlorophenyl)furan-2-carboxylic acid
OverviewOverview
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).
About this StructureAbout this Structure
2EVM is a Single protein structure of sequence from Escherichia coli with MN, NA and FC2 as ligands. Active as Methionyl aminopeptidase, with EC number 3.4.11.18 Full crystallographic information is available from OCA.
ReferenceReference
Structural analysis of metalloform-selective inhibition of methionine aminopeptidase., Xie SX, Huang WJ, Ma ZQ, Huang M, Hanzlik RP, Ye QZ, Acta Crystallogr D Biol Crystallogr. 2006 Apr;62(Pt 4):425-32. Epub 2006, Mar 18. PMID:16552144
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