4O3T: Zymogen Hgf-beta/met With Zymogen Activator Peptide Zap.14

Citation:
Abstract
Stimulation of hepatocyte growth factor (HGF) signaling through the Met receptor is an attractive approach for promoting tissue repair and preventing fibrosis. Using structure-guided peptide phage display combined with an activity-based sorting strategy, we engineered allosteric activators of zymogen-like pro-HGF to bypass proteolytic activation and reversibly stimulate pro-HGF signaling through Met. Biochemical, structural and biological data showed that zymogen activator peptides (ZAPtides) potently and selectively bind the activation pocket within the serine protease-like beta-chain of pro-HGF and display titratable activation of pro-HGF-dependent Met signaling, leading to cell survival and migration. To further demonstrate the versatility of our ZAPtide platform, we identified allosteric activators for pro-macrophage stimulating protein and a zymogen serine protease, Protein C, which also provides evidence for target selectivity. These studies reveal that ZAPtides use molecular mimicry of the trypsin-like N-terminal insertion mechanism and establish a new paradigm for selective pharmacological activation of plasminogen-related growth factors and zymogen serine proteases.
PDB ID: 4O3TDownload
MMDB ID: 120472
PDB Deposition Date: 2013/12/18
Updated in MMDB: 2014/07
Experimental Method:
x-ray diffraction
Resolution: 2.99  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4O3T: trimeric; determined by author
Molecular Components in 4O3T
Label Count Molecule
Proteins (3 molecules)
1
Hepatocyte Growth Factor(Gene symbol: HGF)
Molecule annotation
1
Hepatocyte Growth Factor Receptor(Gene symbol: MET)
Molecule annotation
1
Zap.14
Molecule annotation
Chemicals (4 molecules)
1
1
2
2
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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