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PDBsum entry 4o3t
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Transferase/growth factor
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PDB id
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4o3t
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References listed in PDB file
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Key reference
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Title
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An allosteric switch for pro-Hgf/met signaling using zymogen activator peptides.
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Authors
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K.E.Landgraf,
M.Steffek,
C.Quan,
J.Tom,
C.Yu,
L.Santell,
H.R.Maun,
C.Eigenbrot,
R.A.Lazarus.
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Ref.
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Nat Chem Biol, 2014,
10,
567-573.
[DOI no: ]
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PubMed id
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Abstract
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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.
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