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PDBsum entry 1ajq
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Antibiotic resistance
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PDB id
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1ajq
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Ligand-Induced conformational change in penicillin acylase.
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Authors
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S.H.Done,
J.A.Brannigan,
P.C.Moody,
R.E.Hubbard.
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Ref.
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J Mol Biol, 1998,
284,
463-475.
[DOI no: ]
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PubMed id
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Abstract
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The enzyme penicillin acylase (penicillin amidohydrolase EC 3.5.1. 11) catalyses
the cleavage of the amide bond in the benzylpenicillin (penicillin G) side-chain
to produce phenylacetic acid and 6-aminopenicillanic acid (6-APA). The enzyme is
of great pharmaceutical importance, as the product 6-APA is the starting point
for the synthesis of many semi-synthetic penicillin antibiotics. Studies have
shown that the enzyme is specific for hydrolysis of phenylacetamide derivatives,
but is more tolerant of features in the rest of the substrate. It is this
property that has led to many other applications for the enzyme, and greater
knowledge of the enzyme's structure and specificity could facilitate engineering
of the enzyme, enhancing its potential for chemical and industrial
applications.An extensive study of the binding of a series of phenylacetic acid
derivatives has been carried out. A measure of the relative degree of inhibition
of the enzyme by each of the compounds has been obtained using a competitive
inhibition assay, and the structures of a number of these complexes have been
determined by X-ray crystallography. The structures reveal a clear rationale for
the observed kinetic results, but show also that some of the ligands cause a
conformational change within the binding pocket. This change can generally be
understood in terms of the size and orientation of the ligand within the active
site.The results reveal that ligand binding in penicillin acylase is facilitated
by certain amino acid residues that can adopt two distinct, energetically
favourable positions in order to accommodate a variety of compounds within the
active site. The structures of these complexes provide evidence for
conformational changes in the substrate-binding region that may act as a switch
in the mechanism of autocatalytic processing of this enzyme.
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Figure 2.
Figure 2. Views showing the electron density and important
interactions within the binding site for each of the complexes
of the phenylacetic acid derivatives with penicillin acylase.
Electron density is a 2F[o] - F[c] map contoured at 1s. Water
molecules, where shown, are those that interact with the ligand,
and are labelled consistently.
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Figure 4.
Figure 4. (a) Stereo representation of
p-hydroxyphenylacetic acid from subset 1 (white) and
p-nitrophenylacetic from subset 2 (black) structures overlaid
and the interactions made by each ligand. Hydrogen bonds for
p-nitrophenylacetic acid are shown as dotted lines and H-bonds
for the p-hydroxyphenylacetic acid are shown as broken lines.
(b) Close up of the overlaid ligand positions from (a).
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(1998,
284,
463-475)
copyright 1998.
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Secondary reference #1
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Title
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Author
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S.H.Done.
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Ref.
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structural studies of ...
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Secondary reference #2
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Title
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Penicillin acylase has a single-Amino-Acid catalytic centre.
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Authors
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H.J.Duggleby,
S.P.Tolley,
C.P.Hill,
E.J.Dodson,
G.Dodson,
P.C.Moody.
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Ref.
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Nature, 1995,
373,
264-268.
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PubMed id
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Secondary reference #3
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Title
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Expression, Purification and crystallization of penicillin g acylase from escherichia coli atcc 11105.
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Authors
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P.D.Hunt,
S.P.Tolley,
R.J.Ward,
C.P.Hill,
G.G.Dodson.
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Ref.
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Protein Eng, 1990,
3,
635-639.
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PubMed id
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