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PDBsum entry 1g2l
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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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Structural basis for inhibition promiscuity of dual specific thrombin and factor xa blood coagulation inhibitors.
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Authors
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H.Nar,
M.Bauer,
A.Schmid,
J.M.Stassen,
W.Wienen,
H.W.Priepke,
I.K.Kauffmann,
U.J.Ries,
N.H.Hauel.
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Ref.
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Structure, 2001,
9,
29-37.
[DOI no: ]
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PubMed id
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Abstract
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BACKGROUND: A major current focus of pharmaceutical research is the development
of selective inhibitors of the blood coagulation enzymes thrombin or factor Xa
to be used as orally bioavailable anticoagulant drugs in thromboembolic
disorders and in the prevention of venous and arterial thrombosis. Simultaneous
direct inhibition of thrombin and factor Xa by synthetic proteinase inhibitors
as a novel approach to antithrombotic therapy could result in potent
anticoagulants with improved pharmacological properties. RESULTS: The binding
mode of such dual specific inhibitors of thrombin and factor Xa was determined
for the first time by comparative crystallography using human alpha-thrombin,
human des-Gla (1--44) factor Xa and bovine trypsin as the ligand receptors. The
benzamidine-based inhibitors utilize two different conformations for the
interaction with thrombin and factor Xa/trypsin, which are evoked by the steric
requirements of the topologically different S2 subsites of the enzymes. Compared
to the unliganded forms of the proteinases, ligand binding induces
conformational adjustments of thrombin and factor Xa active site residues
indicative of a pronounced induced fit mechanism. CONCLUSION: The structural
data reveal the molecular basis for a desired unselective inhibition of the two
key components of the blood coagulation cascade. The
4-(1-methyl-benzimidazole-2-yl)-methylamino-benzamidine moieties of the
inhibitors are able to fill both the small solvent accessible as well as the
larger hydrophobic S2 pockets of factor Xa and thrombin, respectively. Distal
fragments of the inhibitors are identified which fit into both the cation
hole/aromatic box of factor Xa and the hydrophobic aryl binding site of
thrombin. Thus, binding constants in the medium-to-low nanomolar range are
obtained against both enzymes.
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Figure 2.
Figure 2. Experimental Evidence for the Bound Conformation
of the Ligands to their Protein ReceptorsDifference electron
density maps (contoured at 2s) of BIBT0871 (left column) and
BIBR1109 (right column) in the active sites of factor Xa,
trypsin and thrombin (from top to bottom) superimposed on the
final structures
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2001,
9,
29-37)
copyright 2001.
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