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  • Title: The three-dimensional structures of tick carboxypeptidase inhibitor in complex with A/B carboxypeptidases reveal a novel double-headed binding mode.
    Author: Arolas JL, Popowicz GM, Lorenzo J, Sommerhoff CP, Huber R, Aviles FX, Holak TA.
    Journal: J Mol Biol; 2005 Jul 15; 350(3):489-98. PubMed ID: 15961103.
    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 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.
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