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PDBsum entry 4jpm
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Hydrolase/hydrolase inhibitor
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PDB id
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4jpm
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References listed in PDB file
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Key reference
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Title
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β-Lactamase inhibition by 7-Alkylidenecephalosporin sulfones: allylic transposition and formation of an unprecedented stabilized acyl-Enzyme.
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Authors
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E.A.Rodkey,
D.C.Mcleod,
C.R.Bethel,
K.M.Smith,
Y.Xu,
W.Chai,
T.Che,
P.R.Carey,
R.A.Bonomo,
F.Van den akker,
J.D.Buynak.
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Ref.
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J Am Chem Soc, 2013,
135,
18358-18369.
[DOI no: ]
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PubMed id
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Abstract
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The inhibition of the class A SHV-1 β-lactamase by
7-(tert-butoxycarbonyl)methylidenecephalosporin sulfone was examined
kinetically, spectroscopically, and crystallographically. An 1.14 Å X-ray
crystal structure shows that the stable acyl-enzyme, which incorporates an
eight-membered ring, is a covalent derivative of Ser70 linked to the 7-carboxy
group of 2-H-5,8-dihydro-1,1-dioxo-1,5-thiazocine-4,7-dicarboxylic acid. A
cephalosporin-derived enzyme complex of this type is unprecedented, and the
rearrangement leading to its formation may offer new possibilities for inhibitor
design. The observed acyl-enzyme derives its stability from the resonance
stabilization conveyed by the β-aminoacrylate (i.e., vinylogous urethane)
functionality as there is relatively little interaction of the eight-membered
ring with active site residues. Two mechanistic schemes are proposed, differing
in whether, subsequent to acylation of the active site serine and opening of the
β-lactam, the resultant dihydrothiazine fragments on its own or is assisted by
an adjacent nucleophilic atom, in the form of the carbonyl oxygen of the C7
tert-butyloxycarbonyl group. This compound was also found to be a submicromolar
inhibitor of the class C ADC-7 and PDC-3 β-lactamases.
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