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PDBsum entry 3e2k
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Hydrolase/hydrolase inhibitor
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PDB id
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3e2k
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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 and biochemical characterization of the interaction between kpc-2 beta-Lactamase and beta-Lactamase inhibitor protein.
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Authors
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M.S.Hanes,
K.M.Jude,
J.M.Berger,
R.A.Bonomo,
T.M.Handel.
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Ref.
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Biochemistry, 2009,
48,
9185-9193.
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PubMed id
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Abstract
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KPC beta-lactamases hydrolyze the "last resort" beta-lactam antibiotics
(carbapenems) used to treat multidrug resistant infections and are compromising
efforts to combat life-threatening Gram-negative bacterial infections in
hospitals worldwide. Consequently, the development of novel inhibitors is
essential for restoring the effectiveness of existing antibiotics. The
beta-lactamase inhibitor protein (BLIP) is a competitive inhibitor of a number
of class A beta-lactamases. In this study, we characterize the previously
unreported interaction between KPC-2 beta-lactamase and BLIP. Biochemical
results show that BLIP is an extremely potent inhibitor of KPC enzymes, binding
KPC-2 and KPC-3 with subnanomolar affinity. To understand the basis of affinity
and specificity in the beta-lactamase-BLIP system, the crystallographic
structure of the KPC-2-BLIP complex was determined to 1.9 A resolution.
Computational alanine scanning was also conducted to identify putative hot spots
in the KPC-2-BLIP interface. Interestingly, the two complexes making up the
KPC-2-BLIP asymmetric unit are distinct, and in one structure, the BLIP F142
loop is absent, in contrast to homologous structures in which it occupies the
active site. This finding and other sources of structural plasticity appear to
contribute to BLIP's promiscuity, enabling it to respond to mutations at the
beta-lactamase interface. Given the continuing emergence of antibiotic
resistance, the high-resolution KPC-2-BLIP structure will facilitate its use as
a template for the rational design of new inhibitors of this problematic enzyme.
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