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PDBsum entry 1bhx
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Serine protease
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PDB id
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1bhx
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Contents |
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30 a.a.
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147 a.a.
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105 a.a.
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* Residue conservation analysis
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PDB id:
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| Name: |
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Serine protease
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Title:
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X-ray structure of the complex of human alpha thrombin with the inhibitor sdz 229-357
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Structure:
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Alpha thrombin. Chain: a. Alpha thrombin. Chain: b. Alpha thrombin. Chain: f. Alpha thrombin. Chain: e. Ec: 3.4.21.5
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Organism_taxid: 9606
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Biol. unit:
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Tetramer (from
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Resolution:
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2.30Å
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R-factor:
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0.187
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R-free:
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0.232
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Authors:
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J.Kallen
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Key ref:
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J.Wagner
et al.
(1998).
Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors.
J Med Chem,
41,
3664-3674.
PubMed id:
DOI:
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Date:
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10-Jun-98
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Release date:
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04-Nov-98
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PROCHECK
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Headers
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References
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P00734
(THRB_HUMAN) -
Prothrombin from Homo sapiens
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Seq:
Struc:
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622 a.a.
30 a.a.
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Enzyme class:
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Chains A, B, F:
E.C.3.4.21.5
- thrombin.
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Reaction:
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Preferential cleavage: Arg-|-Gly; activates fibrinogen to fibrin and releases fibrinopeptide A and B.
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DOI no:
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J Med Chem
41:3664-3674
(1998)
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PubMed id:
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Rational design, synthesis, and X-ray structure of selective noncovalent thrombin inhibitors.
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J.Wagner,
J.Kallen,
C.Ehrhardt,
J.P.Evenou,
D.Wagner.
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ABSTRACT
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We have designed, synthesized, and tested in vitro a novel class of noncovalent
thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused
bicyclic core structure that fills the S2 pocket of the active site of thrombin.
The bicycle introduces conformational constraint into the ligand and locks the
Xaa-Pro amide bond into the desired trans configuration. Among the known ring
systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as
our basic template. The influence of several structural features was analyzed:
the length of the argininal side chain, the stereochemistry at C6, and the
importance of making optimal use of the S3 pocket. Finally, an X-ray crystal
structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3
A. These designed thrombin inhibitors, which were prepared by an efficient
synthesis, showed high selectivity over trypsin and other serine proteases.
Further derivation based on the information obtained by X-ray crystallography
should certainly allow to improve the potency.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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W.H.Chiou,
N.Mizutani,
and
I.Ojima
(2007).
Highly efficient synthesis of azabicyclo[x.y.0]alkane amino acids and congeners by means of Rh-catalyzed cyclohydrocarbonylation.
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J Org Chem,
72,
1871-1882.
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E.Toyota,
H.Sekizaki,
Y.U.Takahashi,
K.Itoh,
and
K.Tanizawa
(2005).
Amidino-containing Schiff base copper(II) and iron(III) chelates as a thrombin inhibitor.
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Chem Pharm Bull (Tokyo),
53,
22-26.
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J.Cluzeau,
and
W.D.Lubell
(2005).
Design, synthesis, and application of azabicyclo[X.Y.0]alkanone amino acids as constrained dipeptide surrogates and peptide mimics.
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Biopolymers,
80,
98.
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S.Srivastava,
L.N.Goswami,
and
D.K.Dikshit
(2005).
Progress in the design of low molecular weight thrombin inhibitors.
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Med Res Rev,
25,
66-92.
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A.von Matt,
C.Ehrhardt,
P.Burkhard,
R.Metternich,
M.Walkinshaw,
and
C.Tapparelli
(2000).
Selective boron-containing thrombin inhibitors--X-ray analysis reveals surprising binding mode.
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Bioorg Med Chem,
8,
2291-2303.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
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Links
