Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Drug
Enzyme
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Query: EC:3.4.21.6 (
thromboplastin
)
13,278
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Stromal cell-derived
FGF-7
binds and activates only the resident FGFR2IIIb in epithelial cells while FGF-1 and FGF-2 exhibit a broader interaction with multiple isoforms of FGFR. Here we report the structure of
FGF-7
that has been solved to 3.1 A resolution by molecular replacement with the structure of a dual function chimera of
FGF-7
and FGF-1 (
FGF-7
/1) which was resolved to 2.3 A. Comparison of the
FGF-7
structure to that of FGF-1 and FGF-2 revealed the strongly conserved Calpha backbone among the three FGF polypeptides and the surface hydrophobic patch that forms the primary receptor-binding domain. In contrast, a decrease and dispersion of the positive surface charge density characterized the heparin-binding domain of
FGF-7
defined by homology to that of FGF-1 and FGF-2 in complexes with heparin. A simple heparin hexasaccharide that cocrystallized with FGF-1 and FGF-2 and protected both against protease in solution failed to exhibit the same properties with
FGF-7
. In contrast to FGF-1 and FGF-2, protection of
FGF-7
was enhanced by heparin oligosaccharides of increased length with those exhibiting a 3-O-sulfate being the most effective. Protection of
FGF-7
required interaction with specifically the fraction of crude heparin retained on antithrombin affinity columns. Conversely, heparin enriched by affinity for immobilized
FGF-7
exhibited anti-
factor Xa
activity similar to that purified on an antithrombin affinity matrix. In contrast, an FGF-1 affinity matrix enriched the fraction of crude heparin with low anti-
factor Xa
activity. The results provide a structural basis to suggest that the unique
FGF-7
heparin-binding (HB) domain underlies a specific restriction in respect to composition and length of the heparan sulfate motif that may impact specificity of localization, stability, and trafficking of
FGF-7
in the microenvironment, and formation and activation of the FGFR2IIIb kinase signaling complex in epithelial cells.
...
PMID:Structural basis for interaction of FGF-1, FGF-2, and FGF-7 with different heparan sulfate motifs. 1172 55
Oral mucositis, a severe complication during chemo- and/or radiotherapy, is prevented with palifermin treatment, a recombinant human
keratinocyte growth factor
(
KGF
/
FGF-7
). The FGF family belongs to the larger family of heparin-binding growth factors. Because it has been shown that heparin modulates binding of
KGF
to the
KGF
receptor and subsequently affects cellular proliferation induced by the
KGF
mitogenic signal, it is critical to understand the drug-drug interactions between palifermin and heparin, particularly because of heparin's narrow therapeutic margin. Two studies were performed in healthy subjects to characterize the effect of palifermin on the pharmacodynamics of heparin (activated partial
thromboplastin
time) and evaluate the impact of heparin on the pharmacokinetics and pharmacodynamics (Ki67 staining of buccal mucosal tissue) of palifermin. Results demonstrated a pronounced pharmacokinetic interaction; heparin coadministration increased the palifermin AUC 4- to 5-fold and decreased its half-life by 40%-45%, suggesting an approximate 70%-80% decrease in palifermin clearance and volume of distribution. These changes in the pharmacokinetics of palifermin during coadministration of heparin, however, did not affect the pharmacodynamic effect of palifermin, or the anticoagulant activity of heparin, and did not lead to increased safety findings. Therefore, these results suggest that dose adjustments for heparin and palifermin are not warranted when administered concurrently.
...
PMID:Pharmacokinetic and pharmacodynamic interactions between palifermin and heparin. 2588 Aug 26
