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PDBsum entry 1blh
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Hydrolase(beta-lactamase)
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PDB id
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1blh
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References listed in PDB file
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Key reference
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Title
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Structure of a phosphonate-Inhibited beta-Lactamase. An analog of the tetrahedral transition state/intermediate of beta-Lactam hydrolysis.
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Authors
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C.C.Chen,
J.Rahil,
R.F.Pratt,
O.Herzberg.
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Ref.
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J Mol Biol, 1993,
234,
165-178.
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PubMed id
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Abstract
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The crystal structure of beta-lactamase from Staphylococcus aureus inactivated
by p-nitrophenyl[[N-(benzyloxycarbonyl)amino]methyl]phosphonate, a
methylphosphonate monoester monoanion inhibitor, has been determined and refined
at 2.3 A resolution. The structure reveals a tetrahedral phosphorus covalently
bonded to the O gamma atom of the active site serine, Ser70. One of the oxygen
atoms bonded to phosphorus is located in the oxyanion hole formed by the two
main-chain nitrogen atoms of Ser70 and Gln237, and the second bonded oxygen is
solvated. The (benzyloxycarbonyl)aminomethyl group is oriented towards the
active site gully such that the peptide group forms compensating electrostatic
interactions with polar groups on the enzyme. The benzyl group forms a
hydrophobic interaction with Ile239 and an aromatic-aromatic edge-to-face
interaction with Tyr105, which has undergone a conformational transition
relative to the native structure. The mode of binding supports the proposal that
on reaction with the enzyme, the phosphonate generates a structure analogous to
the tetrahedral transition state/intermediate associated with the acylation step
of a normal substrate. The disposition of the phosphonyl group in this complex
is the same as that of the corresponding phosphoryl group in the complex
resulting from the inhibition of trypsin by diisopropylphosphofluoridate. The
structure is consistent with a mechanism of inactivation that follows an
associative pathway, proceeding via a transition state/intermediate in which
phosphorus is penta-co-ordinated, forming a trigonal bipyramidal geometry with
the phosphonyl donor (p-nitrophenol) and acceptor (Ser70 O gamma atom) in apical
positions. A model of this transition state can be accommodated in the active
site of beta-lactamase without any steric hindrance. A model of the tetrahedral
transition state associated with the acylation step by benzyl penicillin has
been derived. Because of the conformational rigidity of the fused rings of
penicillin molecules, the orientation of the substrate is fixed once the
tetrahedral carbonyl carbon and its ligands are superimposed on the phosphonate
group. The outcome is that the carboxylate substituent on the thiazolidine ring
forms a salt bridge with Lys234, and the preferred puckering of the ring is that
observed in the crystal structure of ampicillin, the so-called "open" conformer.
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Secondary reference #1
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Title
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Inhibition of beta-Lactamase by clavulanate. Trapped intermediates in cryocrystallographic studies.
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Authors
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C.C.Chen,
O.Herzberg.
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Ref.
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J Mol Biol, 1992,
224,
1103-1113.
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PubMed id
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Secondary reference #2
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Title
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Refined crystal structure of beta-Lactamase from staphylococcus aureus pc1 at 2.0 a resolution.
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Author
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O.Herzberg.
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Ref.
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J Mol Biol, 1991,
217,
701-719.
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PubMed id
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Secondary reference #3
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Title
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Structural basis for the inactivation of the p54 mutant of beta-Lactamase from staphylococcus aureus pc1.
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Authors
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O.Herzberg,
G.Kapadia,
B.Blanco,
T.S.Smith,
A.Coulson.
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Ref.
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Biochemistry, 1991,
30,
9503-9509.
[DOI no: ]
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PubMed id
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Secondary reference #4
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Title
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Penicillin-Binding and degrading enzymes
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Authors
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O.Herzberg,
J.Moult.
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Ref.
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curr opin struct biol, 1991,
1,
946.
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Secondary reference #5
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Title
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Bacterial resistance to beta-Lactam antibiotics: crystal structure of beta-Lactamase from staphylococcus aureus pc1 at 2.5 a resolution.
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Authors
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O.Herzberg,
J.Moult.
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Ref.
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Science, 1987,
236,
694-701.
[DOI no: ]
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PubMed id
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Secondary reference #6
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Title
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The crystal structure of beta-Lactamase from staphylococcus aureus at 0.5 nm resolution.
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Authors
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J.Moult,
L.Sawyer,
O.Herzberg,
C.L.Jones,
A.F.Coulson,
D.W.Green,
M.M.Harding,
R.P.Ambler.
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Ref.
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Biochem J, 1985,
225,
167-176.
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PubMed id
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