4O3U

Zymogen HGF-beta/MET with Zymogen Activator Peptide ZAP2.3


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.04 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides.

Landgraf, K.E.Steffek, M.Quan, C.Tom, J.Yu, C.Santell, L.Maun, H.R.Eigenbrot, C.Lazarus, R.A.

(2014) Nat Chem Biol 10: 567-573

  • DOI: https://doi.org/10.1038/nchembio.1533
  • Primary Citation of Related Structures:  
    4O3T, 4O3U

  • 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.


  • Organizational Affiliation

    1] Department of Early Discovery Biochemistry, Genentech, Inc., San Francisco, California, USA. [2].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor240Homo sapiensMutation(s): 2 
Gene Names: HGFHPTA
UniProt & NIH Common Fund Data Resources
Find proteins for P14210 (Homo sapiens)
Explore P14210 
Go to UniProtKB:  P14210
PHAROS:  P14210
GTEx:  ENSG00000019991 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP14210
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor receptor551Homo sapiensMutation(s): 0 
Gene Names: MET
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P08581 (Homo sapiens)
Explore P08581 
Go to UniProtKB:  P08581
PHAROS:  P08581
GTEx:  ENSG00000105976 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08581
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
ZAP 2.3C [auth P]15synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.04 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.207 
  • R-Value Observed: 0.209 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 136.105α = 90
b = 139.62β = 90
c = 66.144γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
BUSTERrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-06-04
    Type: Initial release
  • Version 1.1: 2014-07-02
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Refinement description