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Understanding binding selectivity toward trypsin and factor Xa: the role of aromatic interactions.
ChemMedChem. 2007 Mar; 2(3):297-308.C

Abstract

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.

Authors+Show Affiliations

Institute of Pharmaceutical Chemistry, University of Marburg, Marbacher Weg 6, 35032 Marburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17191291

Citation

Di Fenza, Armida, et al. "Understanding Binding Selectivity Toward Trypsin and Factor Xa: the Role of Aromatic Interactions." ChemMedChem, vol. 2, no. 3, 2007, pp. 297-308.
Di Fenza A, Heine A, Koert U, et al. Understanding binding selectivity toward trypsin and factor Xa: the role of aromatic interactions. ChemMedChem. 2007;2(3):297-308.
Di Fenza, A., Heine, A., Koert, U., & Klebe, G. (2007). Understanding binding selectivity toward trypsin and factor Xa: the role of aromatic interactions. ChemMedChem, 2(3), 297-308.
Di Fenza A, et al. Understanding Binding Selectivity Toward Trypsin and Factor Xa: the Role of Aromatic Interactions. ChemMedChem. 2007;2(3):297-308. PubMed PMID: 17191291.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Understanding binding selectivity toward trypsin and factor Xa: the role of aromatic interactions. AU - Di Fenza,Armida, AU - Heine,Andreas, AU - Koert,Ulrich, AU - Klebe,Gerhard, PY - 2006/12/28/pubmed PY - 2008/7/25/medline PY - 2006/12/28/entrez SP - 297 EP - 308 JF - ChemMedChem JO - ChemMedChem VL - 2 IS - 3 N2 - 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. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/17191291/Understanding_binding_selectivity_toward_trypsin_and_factor_Xa:_the_role_of_aromatic_interactions_ L2 - https://doi.org/10.1002/cmdc.200600185 DB - PRIME DP - Unbound Medicine ER -