PDBsum entry 4o3t

Transferase/growth factor

PDB id: 4o3t

Contents

Protein chains

219 a.a.

499 a.a.

Ligands

ILE-VAL-GLY-GLY-TYR-PRO-TRP-TRP-MET

NAG-FUC-NAG

1PE

PDB id:

4o3t

Name:

Transferase/growth factor

Title:

Zymogen hgf-beta/met with zymogen activator peptide zap.14

Structure:

Hepatocyte growth factor. Chain: a. Fragment: hgf-beta (unp residues 25-567). Synonym: hepatopoietin-a, scatter factor, sf, hepatocyte growth factor alpha chain, hepatocyte growth factor beta chain. Engineered: yes. Mutation: yes. Hepatocyte growth factor receptor. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: hgf, hpta. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: met. Synthetic: yes. Synthetic.

Resolution:

2.99Å R-factor: 0.233 R-free: 0.276

Authors:

C.Eigenbrot,K.E.Landgraf,M.Steffek

Key ref:

K.E.Landgraf et al. (2014). An allosteric switch for pro-HGF/Met signaling using zymogen activator peptides. Nat Chem Biol, 10, 567-573. PubMed id: 24859116 DOI: 10.1038/nchembio.1533

Date:

18-Dec-13 Release date: 04-Jun-14

Protein chain

P14210  (HGF_HUMAN) -  Hepatocyte growth factor from Homo sapiens

Seq: 728 a.a.

Struc: 219 a.a.*

Protein chain

P08581  (MET_HUMAN) -  Hepatocyte growth factor receptor from Homo sapiens

Seq: 1390 a.a.

Struc: 499 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chain B: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = NAG) matches with 41.38% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1038/nchembio.1533

Nat Chem Biol 10:567-573 (2014)

PubMed id: 24859116

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

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

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.