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PDBsum entry 4pqa
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Hydrolase/hydrolase inhibitor
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PDB id
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4pqa
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References listed in PDB file
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Key reference
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Title
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Inhibition of the dape-Encoded n-Succinyl-L,L-Diaminopimelic acid desuccinylase from neisseria meningitidis by l-Captopril.
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Authors
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A.Starus,
B.Nocek,
B.Bennett,
J.A.Larrabee,
D.L.Shaw,
W.Sae-Lee,
M.T.Russo,
D.M.Gillner,
M.Makowska-Grzyska,
A.Joachimiak,
R.C.Holz.
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Ref.
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Biochemistry, 2015,
54,
4834-4844.
[DOI no: ]
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PubMed id
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Abstract
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Binding of the competitive inhibitor L-captopril to the dapE-encoded
N-succinyl-L,L-diaminopimelic acid desuccinylase from Neisseria meningitidis
(NmDapE) was examined by kinetic, spectroscopic, and crystallographic methods.
L-Captopril, an angiotensin-converting enzyme (ACE) inhibitor, was previously
shown to be a potent inhibitor of the DapE from Haemophilus influenzae (HiDapE)
with an IC50 of 3.3 μM and a measured Ki of 1.8 μM and displayed a
dose-responsive antibiotic activity toward Escherichia coli. L-Captopril is also
a competitive inhibitor of NmDapE with a Ki of 2.8 μM. To examine the nature of
the interaction of L-captopril with the dinuclear active site of DapE, we have
obtained electron paramagnetic resonance (EPR) and magnetic circular dichroism
(MCD) data for the enzymatically hyperactive Co(II)-substituted forms of both
HiDapE and NmDapE. EPR and MCD data indicate that the two Co(II) ions in DapE
are antiferromagnetically coupled, yielding an S = 0 ground state, and suggest a
thiolate bridge between the two metal ions. Verification of a thiolate-bridged
dinuclear complex was obtained by determining the three-dimensional X-ray
crystal structure of NmDapE in complex with L-captopril at 1.8 Å resolution.
Combination of these data provides new insights into binding of L-captopril to
the active site of DapE enzymes as well as important inhibitor-active site
residue interaction's. Such information is critical for the design of new,
potent inhibitors of DapE enzymes.
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