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Title
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Structural and functional analyses of benzamidine-based inhibitors in complex with trypsin: implications for the inhibition of factor Xa, tPA, and urokinase.
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Authors
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M.Renatus,
W.Bode,
R.Huber,
J.Stürzebecher,
M.T.Stubbs.
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Ref.
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J Med Chem, 1998,
41,
5445-5456.
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PubMed id
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Abstract
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The trypsin-like serine proteinase superfamily contains a number of potential
therapeutic targets, many of which are unsuitable for routine X-ray
crystallographic studies. We have cocrystallized a selection of
benzamidine-based inhibitors with bovine trypsin and solved their structures to
a resolution of up to 1.7 A. Despite similar chemical formulas, the inhibitors
exhibit a range of diverse binding modes that reflect their inhibitory spectra
against the serine proteinases trypsin, thrombin, factor Xa, tissue-type
plasminogen activator (tPA) and urokinase (uPA). In contrast to the compact
folded conformations of thrombin inhibitors which allow optimal binding in the
well-defined hydrophobic S2/S4 pocket of thrombin, those effective against
factor Xa exhibit an extended conformation that allows occupation of the S3/S4
region, where hydrophobic and electrostatic interactions can stabilize the
conformation. One group of inhibitors containing an N-terminal 2,4,
6-triisopropylphenylsulfonyl (TIPPS) moiety show little or no penetration into
the S3/S4 subsites of trypsin. These latter sites are occluded in uPA,
explaining why this class of compounds is effective against uPA. Despite
presenting an extensive hydrophobic surface toward the solvent, the Ki values
for TIPPS-containing compounds against trypsin is in the range 10(-7) to 10(-8)
M. Comparison of the binding of a bis-benzamidine inhibitor in trypsin and tPA
indicate that a shift in potency can be induced by relatively minor changes in
binding mode. Implications for the inhibition of these proteinases are discussed.
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