The three-dimensional structures of tick carboxypeptidase inhibitor in complex with A/B carboxypeptidases reveal a novel double-headed binding mode

Joan L. Arolas, Grzegorz M. Popowicz, Julia Lorenzo, Christian P. Sommerhoff, Robert Huber, Francesc X. Aviles, Tad A. Holak

Research output: Contribution to journalArticleResearchpeer-review

53 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)489-498
JournalJournal of Molecular Biology
Volume350
DOIs
Publication statusPublished - 15 Jul 2005

Keywords

  • Carboxypeptidase inhibitor
  • Crystal structure
  • Inhibitor-enzyme complex
  • Metallo-carboxypeptidase
  • Pro-fibrinolytic drug

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