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PDBsum entry 1tmt
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Hydrolase/hydrolase inhibitor
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PDB id
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1tmt
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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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Changes in interactions in complexes of hirudin derivatives and human alpha-Thrombin due to different crystal forms.
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Authors
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J.P.Priestle,
J.Rahuel,
H.Rink,
M.Tones,
M.G.Grütter.
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Ref.
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Protein Sci, 1993,
2,
1630-1642.
[DOI no: ]
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PubMed id
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Abstract
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The three-dimensional structures of D-Phe-Pro-Arg-chloromethyl ketone-inhibited
thrombin in complex with Tyr-63-sulfated hirudin (ternary complex) and of
thrombin in complex with the bifunctional inhibitor
D-Phe-Pro-Arg-Pro-(Gly)4-hirudin (CGP 50,856, binary complex) have been
determined by X-ray crystallography in crystal forms different from those
described by Skrzypczak-Jankun et al. (Skrzypczak-Jankun, E., Carperos, V.E.,
Ravichandran, K.G., & Tulinsky, A., 1991, J. Mol. Biol. 221, 1379-1393). In
both complexes, the interactions of the C-terminal hirudin segments of the
inhibitors binding to the fibrinogen-binding exosite of thrombin are clearly
established, including residues 60-64, which are disordered in the earlier
crystal form. The interactions of the sulfate group of Tyr-63 in the ternary
complex structure explain why natural sulfated hirudin binds with a 10-fold
lower K(i) than the desulfated recombinant material. In this new crystal form,
the autolysis loop of thrombin (residues 146-150), which is disordered in the
earlier crystal form, is ordered due to crystal contacts. Interactions between
the C-terminal fragment of hirudin and thrombin are not influenced by crystal
contacts in this new crystal form, in contrast to the earlier form. In the
bifunctional inhibitor-thrombin complex, the peptide bond between Arg-Pro
(P1-P1') seems to be cleaved.
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Figure 6.
Fig. 6. Residues h55-h58 of CGP
50,856 (solid bonds) with electron
density in the exosite of thrombin
(open bonds). The 2.2 2F0 - F,, UA
(Read, 1986) electrondensitycon-
toured at 1 rms above the meanslowly
fades away beyond theamino side of
residue h55, implying that the Pro-
(Gly), linker of CGP 50,856 as well
as residuh5extends out into the sol-
vent in some disorderly fashionafter
being cleaved. The side chain fh55-
Aspcouldalsonotbeinterpreted
from the electron density.
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Figure 7.
Fig. 7. Conformation of the 149 loop
in thrombin as found in three different
crystal structures: PPACK-inhibited
thrombin (open bonds; Bode et al.,
1989), hirudin-inhibited thrombin
(striped bonds; Grutter et al., 1990),
andCGP 50,856-inhibited thrombin
(solid bonds).
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The above figures are
reprinted
from an Open Access publication published by the Protein Society:
Protein Sci
(1993,
2,
1630-1642)
copyright 1993.
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Secondary reference #1
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Title
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Structure of the hirugen and hirulog 1 complexes of alpha-Thrombin.
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Authors
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E.Skrzypczak-Jankun,
V.E.Carperos,
K.G.Ravichandran,
A.Tulinsky,
M.Westbrook,
J.M.Maraganore.
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Ref.
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J Mol Biol, 1991,
221,
1379-1393.
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PubMed id
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Secondary reference #2
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Title
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Refined structure of the hirudin-Thrombin complex.
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Authors
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T.J.Rydel,
A.Tulinsky,
W.Bode,
R.Huber.
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Ref.
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J Mol Biol, 1991,
221,
583-601.
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PubMed id
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Secondary reference #3
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Title
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Crystal structure of the thrombin-Hirudin complex: a novel mode of serine protease inhibition.
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Authors
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M.G.Grütter,
J.P.Priestle,
J.Rahuel,
H.Grossenbacher,
W.Bode,
J.Hofsteenge,
S.R.Stone.
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Ref.
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Embo J, 1990,
9,
2361-2365.
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PubMed id
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Secondary reference #4
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Title
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The refined 1.9 a crystal structure of human alpha-Thrombin: interaction with d-Phe-Pro-Arg chloromethylketone and significance of the tyr-Pro-Pro-Trp insertion segment.
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Authors
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W.Bode,
I.Mayr,
U.Baumann,
R.Huber,
S.R.Stone,
J.Hofsteenge.
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Ref.
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Embo J, 1989,
8,
3467-3475.
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PubMed id
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