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PDBsum entry 1k22
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Hydrolase/hydrolase inhibitor
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PDB id
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1k22
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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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Factorising ligand affinity: a combined thermodynamic and crystallographic study of trypsin and thrombin inhibition.
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Authors
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F.Dullweber,
M.T.Stubbs,
D.Musil,
J.Stürzebecher,
G.Klebe.
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Ref.
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J Mol Biol, 2001,
313,
593-614.
[DOI no: ]
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PubMed id
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Abstract
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The binding of a series of low molecular weight ligands towards trypsin and
thrombin has been studied by isothermal titration calorimetry and protein
crystallography. In a series of congeneric ligands, surprising changes of
protonation states occur and are overlaid on the binding process. They result
from induced pK(a) shifts depending on the local environment experienced by the
ligand and protein functional groups in the complex (induced dielectric fit).
They involve additional heat effects that must be corrected before any
conclusion on the binding enthalpy (DeltaH) and entropy (DeltaS) can be drawn.
After correction, trends in both contributions can be interpreted in structural
terms with respect to the hydrogen bond inventory or residual ligand motions.
For all inhibitors studied, a strong negative heat capacity change (DeltaC(p))
is detected, thus binding becomes more exothermic and entropically less
favourable with increasing temperature. Due to a mutual compensation, Gibbs free
energy remains virtually unchanged. The strong negative DeltaC(p) value cannot
solely be explained by the removal of hydrophobic surface portions of the
protein or ligand from water exposure. Additional contributions must be
considered, presumably arising from modulations of the local water structure,
changes in vibrational modes or other ordering parameters. For thrombin, smaller
negative DeltaC(p) values are observed for ligand binding in the presence of
sodium ions compared to the other alkali ions, probably due to stabilising
effects on the protein or changes in the bound water structure.
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Figure 8.
Figure 8. Alignment of inhibitors 1b (blue) and 2
(white). Trypsin shown by its solvent accessible surface.
The inhibitors were superimposed using the atoms of
amino acid residues His57, Asp102, Asp189 and Ser195
of trypsin or thrombin, respectively. Arrow indicates the
location of the carboxylic groups.
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Figure 12.
Figure 12. Alignment of inhibitors 2 (white) and 3
(orange). Human a-thrombin is shown by its solvent
accessible surface. The inhibitors were superimposed
using the atoms of amino acid residues His57, Asp102,
Asp189 and Ser195 of trypsin or thrombin, respectively.
Arrows indicate the location of the carboxylic groups.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2001,
313,
593-614)
copyright 2001.
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Secondary reference #1
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Title
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Structural and functional analyses of benzamidine-Based inhibitors in complex with trypsin: implications for the inhibition of factor xa, Tpa, And urokinase.
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Authors
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M.Renatus,
W.Bode,
R.Huber,
J.Stürzebecher,
M.T.Stubbs.
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Ref.
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J Med Chem, 1998,
41,
5445-5456.
[DOI no: ]
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PubMed id
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Secondary reference #2
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Title
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Crystal structures of factor xa specific inhibitors in complex with trypsin: structural grounds for inhibition of factor xa and selectivity against thrombin.
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Authors
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M.T.Stubbs,
R.Huber,
W.Bode.
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Ref.
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FEBS Lett, 1995,
375,
103-107.
[DOI no: ]
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PubMed id
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Secondary reference #3
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Title
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A player of many parts: the spotlight falls on thrombin'S structure.
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Authors
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M.T.Stubbs,
W.Bode.
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Ref.
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Thromb Res, 1993,
69,
1.
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PubMed id
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