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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.
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PubMed id
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Abstract
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Crystal structures of DX9065a and a related bisamidino-aryl inhibitor specific
for the blood-clotting factor Xa have been solved in complex with bovine
beta-trypsin to a resolution of 1.9 A. Each inhibitor exhibits an extended
conformation along the active site, in contrast to the compact folded structures
observed for thrombin specific inhibitors. Few direct contacts (predominantly in
the S1 pocket) are made between trypsin and the inhibitors. Transfer of the
inhibitors to the active site of factor Xa suggests a three-site interaction:
salt bridge formation at the base of the primary specificity pocket, extensive
hydrophobic surface burial and a weak electrostatic interaction between the
distal basic component of the inhibitor and an electronegative cavity of factor
Xa formed by three backbone carbonyl oxygens. Additivity of these three
interactions is the basis for the observed strong inhibition of factor Xa and
provides a framework for the design of novel factor Xa inhibitors. A propionic
acid group of the inhibitor would clash with the thrombin specific '60-insertion
loop', thus conferring selectivity against thrombin.
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