The Three-Dimensional Structures of Tick Carboxypeptidase Inhibitor in Complex with A/B Carboxypeptidases Reveal a Novel Double-headed Binding Mode
Copyright policy )The Three-Dimensional Structures of Tick Carboxypeptidase Inhibitor in Complex with A/B Carboxypeptidases Reveal a Novel Double-headed Binding Mode
The tick carboxypeptidase inhibitor (TCI) is a proteinaceous inhibitor of metallo-carboxypeptidases present in the blood-sucking tick Rhipicephalus bursa. The three-dimensional crystal structures of recombinant TCI bound to bovine carboxypeptidase A and to human carboxypeptidase B have been determined and refined at 1.7 A and at 2.0 A resolution, respectively. TCI consists of two domains that are structurally similar despite the low degree of sequence homology. The domains, each consisting of a short alpha-helix followed by a small twisted antiparallel beta-sheet, show a high level of structural homology to proteins of the beta-defensin-fold family. TCI anchors to the surface of mammalian carboxypeptidases in a double-headed manner not previously seen for carboxypeptidase inhibitors: the last three carboxy-terminal amino acid residues interact with the active site of the enzyme in a way that mimics substrate binding, and the N-terminal domain binds to an exosite distinct from the active-site groove. The structures of these complexes should prove valuable in the applications of TCI as a thrombolytic drug and as a basis for the design of novel bivalent carboxypeptidase inhibitors.
- Autonomous University of Barcelona Spain
- Ludwig-Maximilians-Universität München Germany
- Max Planck Institute of Biochemistry Germany
- Max Planck Society Germany
Models, Molecular, Binding Sites, Carboxypeptidases A, Protein Conformation, Amino Acid Motifs, Carboxypeptidases, Crystallography, X-Ray, Carboxypeptidase B, Pichia, Protein Structure, Tertiary, Ticks, Escherichia coli, Rhipicephalus, Animals, Humans, Cattle, Enzyme Inhibitors, Databases, Protein, Pancreas, Protein Binding
Models, Molecular, Binding Sites, Carboxypeptidases A, Protein Conformation, Amino Acid Motifs, Carboxypeptidases, Crystallography, X-Ray, Carboxypeptidase B, Pichia, Protein Structure, Tertiary, Ticks, Escherichia coli, Rhipicephalus, Animals, Humans, Cattle, Enzyme Inhibitors, Databases, Protein, Pancreas, Protein Binding
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