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Selective attenuation of the extrinsic limb of the tissue factor-driven coagulation protease cascade by occupancy of a novel peptidyl docking site on tissue factor.
- Source :
-
Biochemistry [Biochemistry] 2003 Sep 16; Vol. 42 (36), pp. 10619-26. - Publication Year :
- 2003
-
Abstract
- Tissue factor (TF), the receptor and cofactor for factor VIIa (VIIa) for cellular initiation of the coagulation protease cascade, drives thrombogenesis, inflammation, tumor cell metastasis, and the lethality of severe sepsis. To identify TF surface loci that can selectively inhibit substrate zymogen association and activation, TF(1-218), the extracellular domain, was used as the target for the phage display search. This resulted in selection of 59 clones from a phage gpVIII surface protein-expressed library of constrained combinatorial peptides. Of these, one encoding the peptide Glu-Cys-Leu-Arg-Ser-Val-Val-Thr-Cys on gpVIII most avidly bound TF(1-218), as did the synthetic peptide. Inhibition of binding was selective with an IC(50) of 30 nM for proteolytic activation of factor X by the TF(1-218)-VIIa complex. In contrast, there was no inhibition of factor IX activation. The selective inhibition of only factor X association with TF(1-218) will spare the intrinsic hemostatic pathway while attenuating the extrinsic thrombogenic pathway. This and related peptidyl structures provide the potential for the more precise identification of TF surface loci that mediate selective functional properties of the protein as well as a structural basis for the design of novel molecules for selectively attenuating initiation of the extrinsic limb of the coagulation protease cascade and other functions of TF.
- Subjects :
- Amino Acid Sequence
Bacteriophage M13 genetics
Bacteriophage M13 metabolism
Binding Sites
Binding, Competitive
Enzyme Precursors antagonists & inhibitors
Enzyme Precursors metabolism
Factor IX metabolism
Factor VIIa chemistry
Factor VIIa metabolism
Factor X metabolism
Humans
Models, Molecular
Peptide Fragments genetics
Peptide Library
Protein Binding
Protein Structure, Tertiary genetics
Recombinant Proteins chemistry
Recombinant Proteins genetics
Recombinant Proteins metabolism
Thermodynamics
Thromboplastin genetics
Blood Coagulation physiology
Endopeptidases metabolism
Peptide Fragments chemistry
Peptide Fragments metabolism
Thromboplastin chemistry
Thromboplastin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2960
- Volume :
- 42
- Issue :
- 36
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 12962485
- Full Text :
- https://doi.org/10.1021/bi034910f