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 Å and at 2.0 Å 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 α-helix followed by a small twisted antiparallel β-sheet, show a high level of structural homology to proteins of the β-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. © 2005 Elsevier Ltd. All rights reserved.
|Journal||Journal of Molecular Biology|
|Publication status||Published - 15 Jul 2005|
- Carboxypeptidase inhibitor
- Crystal structure
- Inhibitor-enzyme complex
- Pro-fibrinolytic drug
Arolas, J. L., Popowicz, G. M., Lorenzo, J., Sommerhoff, C. P., Huber, R., Aviles, F. X., & Holak, T. A. (2005). The three-dimensional structures of tick carboxypeptidase inhibitor in complex with A/B carboxypeptidases reveal a novel double-headed binding mode. Journal of Molecular Biology, 350, 489-498. https://doi.org/10.1016/j.jmb.2005.05.015