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PDBsum entry 2evc
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References listed in PDB file
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Key reference
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Title
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Structural analysis of metalloform-Selective inhibition of methionine aminopeptidase.
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Authors
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S.X.Xie,
W.J.Huang,
Z.Q.Ma,
M.Huang,
R.P.Hanzlik,
Q.Z.Ye.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2006,
62,
425-432.
[DOI no: ]
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PubMed id
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Abstract
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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).
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Figure 1.
Figure 1 Structures of the inhibitors used for crystallization
and structure solution. Inhibitors (1), (2) and (3) are
MnII-form selective, while inhibitor (4) is CoII-form selective.
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Figure 4.
Figure 4 Stereoviews of inhibitors (2), (3) and (4) at the
enzyme active site. Unbiased F[obs] - F[calc] electron-density
maps showing the inhibitors and metal ions are contoured at 3
 .
(a) The MnII-form selective inhibitor (2) with the MnII-form
enzyme. (b) The MnII-form selective inhibitor (3) with the
MnII-form enzyme. (c) The CoII-form selective inhibitor (4) with
the CoII-form enzyme. For clarity, only the five conserved
residues forming the common dinuclear metal site (Asp97, Asp108,
His171, Glu204 and Glu235) plus His79 and His178 are shown.
Protein residues are colored grey for carbon, red for oxygen and
blue for nitrogen. Inhibitors are colored the same way, except
that carbons are yellow, sulfurs orange, chlorines green and
fluorines cyan. MnII ions are shown as green spheres, while CoII
ions are shown as magenta spheres. Water molecules are shown as
smaller red spheres. Hydrogen bonds and metal interactions are
shown as black dashed lines.
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The above figures are
reprinted
by permission from the IUCr:
Acta Crystallogr D Biol Crystallogr
(2006,
62,
425-432)
copyright 2006.
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