4O3T

Zymogen HGF-beta/MET with Zymogen Activator Peptide ZAP.14

Summary for 4O3T

• Entry DOI: 10.2210/pdb4o3t/pdb
• Descriptor: Hepatocyte growth factor, Hepatocyte growth factor receptor, ZAP.14, ... (5 entities in total)
• Functional Keywords: trypsin homology, receptor activation, transferase-growth factor complex, transferase/growth factor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 91646.41

Authors

Eigenbrot, C.,Landgraf, K.E.,Steffek, M. (deposition date: 2013-12-18, release date: 2014-06-04, Last modification date: 2024-10-09)

Primary citation

Landgraf, K.E.,Steffek, M.,Quan, C.,Tom, J.,Yu, C.,Santell, L.,Maun, H.R.,Eigenbrot, C.,Lazarus, R.A.
An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides.
Nat.Chem.Biol., 10:567-573, 2014

PubMed 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 β-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.

PubMed: 24859116
DOI: 10.1038/nchembio.1533

Experimental method

X-RAY DIFFRACTION (2.99 Å)