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PDBsum entry 1hag
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Hydrolase/hydrolase inhibitor
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PDB id
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1hag
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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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The isomorphous structures of prethrombin2, Hirugen-, And ppack-Thrombin: changes accompanying activation and exosite binding to thrombin.
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Authors
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J.Vijayalakshmi,
K.P.Padmanabhan,
K.G.Mann,
A.Tulinsky.
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Ref.
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Protein Sci, 1994,
3,
2254-2271.
[DOI no: ]
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PubMed id
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Note In the PDB file this reference is
annotated as "TO BE PUBLISHED".
The citation details given above were identified by an automated
search of PubMed on title and author
names, giving a
percentage match of
91%.
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Abstract
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The X-ray crystal structure of prethrombin2 (pre2), the immediate inactive
precursor of alpha-thrombin, has been determined at 2.0 A resolution complexed
with hirugen. The structure has been refined to a final R-value of 0.169 using
14,211 observed reflections in the resolution range 8.0-2.0 A. A total of 202
water molecules have also been located in the structure. Comparison with the
hirugen-thrombin complex showed that, apart from the flexible beginning and
terminal regions of the molecule, there are 4 polypeptide segments in pre2
differing in conformation from the active enzyme (Pro 186-Asp 194, Gly 216-Gly
223, Gly 142-Pro 152, and the Arg 15-Ile 16 cleavage region). The formation of
the Ile 16-Asp 194 ion pair and the specificity pocket are characteristic of
serine protease activation with the conformation of the catalytic triad being
conserved. With the determination of isomorphous structures of hirugen-thrombin
and D-Phe-Pro-Arg chloromethyl ketone (PPACK)-thrombin, the changes that occur
in the active site that affect the kinetics of chromogenic substrate hydrolysis
on binding to the fibrinogen recognition exosite have been determined. The
backbone of the Ala 190-Gly 197 segment in the active site has an average RMS
difference of 0.55 A between the 2 structures (about 3.7 sigma compared to the
bulk structure). This segment has 2 type II beta-bends, the first bend showing
the largest shift due to hirugen binding. Another important feature was the 2
different conformations of the side chain of Glu 192. The side chain extends to
solvent in hirugen-thrombin, which is compatible with the binding of substrates
having an acidic residue in the P3 position (protein-C, thrombin platelet
receptor). In PPACK-thrombin, the side chain of Asp 189 and the segment Arg
221A-Gly 223 move to provide space for the inhibitor, whereas in
hirugen-thrombin, the Ala 190-Gly 197 movement expands the active site region.
Although 8 water molecules are expelled from the active site with PPACK binding,
the inhibitor complex is resolvated with 5 other water molecules.
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Secondary reference #1
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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 #2
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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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