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PDBsum entry 1e35
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Hydrolase(serine protease)
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PDB id
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1e35
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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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'Ph-Jump' Crystallographic analyses of gamma-Lactam-Porcine pancreatic elastase complexes.
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Authors
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P.A.Wright,
R.C.Wilmouth,
I.J.Clifton,
C.J.Schofield.
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Ref.
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Biochem J, 2000,
351,
335-340.
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PubMed id
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Abstract
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beta-Lactams inhibit a range of enzymes via acylation of nucleophilic serine
residues. Certain gamma-lactam analogues of monocyclic beta-lactams have also
been shown to be reversible inhibitors of porcine pancreatic elastase (PPE),
forming acyl-enzyme complexes that are stable with respect to hydrolysis.
Crystallographic analysis at pH 5 of an acyl-enzyme complex formed with PPE and
one of these inhibitors revealed the ester carbonyl located in the oxyanion hole
in a similar conformation to that observed in the structure of a complex formed
between a heptapeptide (beta-casomorphin-7) and PPE. Only weak electron density
was observed for the His-57 side chain in its 'native' conformation. Instead,
the His-57 side chain predominantly adopted a conformation rotated approx. 90
degrees from its normal position. PPE-gamma-lactam crystals were subjected to
'pH-jumps' by placing the crystals in a buffer of increased pH prior to freezing
for data collection. The results indicate that the conformation of the
gamma-lactam-derived acyl-enzyme species in the PPE active site is dependent on
pH, a result having implications for the analysis of other serine
protease-inhibitor structures at non-catalytic pH values. The results help to
define the stereoelectronic relationship between the ester of the acyl-enzyme
complex, the side chain of His-57 and the incoming nucleophile during the
reversible (de)acylation steps, implying it is closely analogous to the
hydrolytic deacylation step during catalytic peptide hydrolysis.
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Secondary reference #1
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Title
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Mechanistic insights into the inhibition of serine proteases by monocyclic lactams.
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Authors
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R.C.Wilmouth,
S.Kassamally,
N.J.Westwood,
R.J.Sheppard,
T.D.Claridge,
R.T.Aplin,
P.A.Wright,
G.J.Pritchard,
C.J.Schofield.
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Ref.
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Biochemistry, 1999,
38,
7989-7998.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Inhibition of elastase by n-Sulfonylaryl beta-Lactams: anatomy of a stable acyl-Enzyme complex.
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Authors
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R.C.Wilmouth,
N.J.Westwood,
K.Anderson,
W.Brownlee,
T.D.Claridge,
I.J.Clifton,
G.J.Pritchard,
R.T.Aplin,
C.J.Schofield.
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Ref.
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Biochemistry, 1998,
37,
17506-17513.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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Structure of a specific acyl-Enzyme complex formed between beta-Casomorphin-7 and porcine pancreatic elastase.
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Authors
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R.C.Wilmouth,
I.J.Clifton,
C.V.Robinson,
P.L.Roach,
R.T.Aplin,
N.J.Westwood,
J.Hajdu,
C.J.Schofield.
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Ref.
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Nat Struct Biol, 1997,
4,
456-462.
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PubMed id
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Secondary reference #4
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Title
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Structure of native porcine pancreatic elastase at 1.65 a resolutions.
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Authors
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E.Meyer,
G.Cole,
R.Radhakrishnan,
O.Epp.
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Ref.
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Acta Crystallogr B, 1988,
44,
26-38.
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PubMed id
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