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PDBsum entry 1y59
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References listed in PDB file
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Key reference
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Title
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Understanding binding selectivity toward trypsin and factor xa: the role of aromatic interactions.
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Authors
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A.Di fenza,
A.Heine,
U.Koert,
G.Klebe.
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Ref.
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Chemmedchem, 2007,
2,
297-308.
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PubMed id
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Abstract
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A congeneric series of four bis-benzamidine inhibitors sharing a dianhydrosugar
isosorbide scaffold in common has been studied by crystal structure analysis and
enzyme kinetics with respect to their binding to trypsin and factor Xa. Within
the series, aromatic interactions are an important determinant for selectivity
discrimination among both serine proteases. To study the selectivity-determining
features in detail, we used trypsin mutants in which the original binding site
is gradually substituted to finally resemble the factor Xa binding pocket. The
influence of these mutations has been analyzed on the binding of the closely
related inhibitors. We present the crystal structures of the inhibitor complexes
obtained by co-crystallizing an "intermediate" trypsin mutant. They could be
determined to a resolution of up to 1.2 A, and we measured the inhibitory
activity (K(i)) of each ligand against factor Xa, trypsin, and the various
mutants. From these data we were able to derive a detailed structure-activity
relationship which demonstrates the importance of aromatic interactions in
protein-ligand recognition and their role in modulating enzyme selectivity.
Pronounced preference is experienced to accommodate the benzamidine anchor with
meta topology in the S(1) specificity pocket. One ligand possessing only para
topology deviates strongly from the other members of the series and adopts a
distinct binding mode addressing the S(1)' site instead of the distal S(3)/S(4)
binding pocket.
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