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PDBsum entry 2ggc
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References listed in PDB file
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Key reference
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Title
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Serendipitous discovery of novel bacterial methionine aminopeptidase inhibitors.
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Authors
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A.G.Evdokimov,
M.Pokross,
R.L.Walter,
M.Mekel,
B.L.Barnett,
J.Amburgey,
W.L.Seibel,
S.J.Soper,
J.F.Djung,
N.Fairweather,
C.Diven,
V.Rastogi,
L.Grinius,
C.Klanke,
R.Siehnel,
T.Twinem,
R.Andrews,
A.Curnow.
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Ref.
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Proteins, 2007,
66,
538-546.
[DOI no: ]
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PubMed id
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Abstract
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In this article we describe the application of structural biology methods to the
discovery of novel potent inhibitors of methionine aminopeptidases. These
enzymes are employed by the cells to cleave the N-terminal methionine from
nascent peptides and proteins. As this is one of the critical steps in protein
maturation, it is very likely that inhibitors of these enzymes may prove useful
as novel antibacterial agents. Involvement of crystallography at the very early
stages of the inhibitor design process resulted in serendipitous discovery of a
new inhibitor class, the pyrazole-diamines. Atomic-resolution structures of
several inhibitors bound to the enzyme illuminate a new mode of inhibitor
binding.
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Figure 2.
Figure 2. Binding of a PDA (compound 3) to EcMAP. (a) chelation
of cobalt atoms (b) mostly hydrophobic interactions between the
PDA and the enzyme active site residues. The inhibitor and
protein residues are shown as stick models with carbon atoms
colored green and yellow, respectively. Cobalt ions are shown as
red spheres. Chelation spheres of Co[-]1 and Co[-]2 are shown as
yellow and magenta dashes, respectively.
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Figure 4.
Figure 4. Interaction of an AA inhibitor with the active site
of EcMAP. The inhibitor and protein residues are shown as stick
models with carbon atoms colored green and yellow, respectively.
Cobalt ions are shown as red spheres. Chelation spheres of Co-1
and Co-2 are shown as yellow and magenta dashes, respectively.
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The above figures are
reprinted
by permission from John Wiley & Sons, Inc.:
Proteins
(2007,
66,
538-546)
copyright 2007.
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