 |
PDBsum entry 5cs9
|
|
|
|
PDB id:
|
|
|
|
| Name: |
|
Hormone
|
|
|
Title:
|
|
The structure of the nk1 fragment of hgf/sf complexed with mes
|
|
Structure:
|
|
Hepatocyte growth factor. Chain: a, b. Fragment: unp residues 28-210. Synonym: hepatopoietin-a,scatter factor,sf. Engineered: yes. Mutation: yes
|
|
Source:
|
|
Homo sapiens. Human. Organism_taxid: 9606. Gene: hgf, hpta. Expressed in: komagataella pastoris cbs 7435. Expression_system_taxid: 981350
|
|
Resolution:
|
|
|
2.00Å
|
R-factor:
|
0.215
|
R-free:
|
0.251
|
|
|
Authors:
|
|
A.G.Sigurdardottir,A.Winter,A.Sobkowicz,M.Fragai,D.Y.Chirgadze, D.B.Ascher,T.L.Blundell,E.Gherardi
|
|
Key ref:
|
|
A.G.Sigurdardottir
et al.
(2015).
Exploring the chemical space of the lysine-binding pocket of the first kringle domain of hepatocyte growth factor/scatter factor (HGF/SF) yields a new class of inhibitors of HGF/SF-MET binding.
Chem Sci,
6,
6147-6157.
PubMed id:
|
|
|
Date:
|
|
|
23-Jul-15
|
Release date:
|
12-Aug-15
|
|
|
|
|
|
|
PROCHECK
|
|
|
|
|
|
Headers
|
|
|
|
References
|
|
|
|
|
|
|
|
P14210
(HGF_HUMAN) -
Hepatocyte growth factor from Homo sapiens
|
|
|
|
Seq:
Struc:
|
|
|
|
728 a.a.
172 a.a.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Key: |
 |
PfamA domain |
|
|
 |
Secondary structure |
|
 |
CATH domain |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
|
|
|
|
|
|
| |
|
|
Chem Sci
6:6147-6157
(2015)
|
|
PubMed id:
|
|
|
|
|
|
| |
|
Exploring the chemical space of the lysine-binding pocket of the first kringle domain of hepatocyte growth factor/scatter factor (HGF/SF) yields a new class of inhibitors of HGF/SF-MET binding.
|
|
A.G.Sigurdardottir,
A.Winter,
A.Sobkowicz,
M.Fragai,
D.Chirgadze,
D.B.Ascher,
T.L.Blundell,
E.Gherardi.
|
|
|
|
|
| |
ABSTRACT
|
|
|
|
| |
|
|
The growth/motility factor hepatocyte growth factor/scatter factor (HGF/SF) and
its receptor, the tyrosine kinase MET, constitute a signalling system essential
for embryogenesis and for tissue/organ regeneration in post-natal life.
HGF/SF-MET signalling, however, also plays a key role in the onset of metastasis
of a large number of human tumours. Both HGF/SF and MET are high molecular
weight proteins that bury an extensive interface upon complex formation and thus
constitute a challenging target for the development of low molecular weight
inhibitors. Here we have used surface plasmon resonance (SPR), nuclear magnetic
resonance (NMR) and X-ray crystallography to screen a diverse fragment library
of 1338 members as well as a range of piperazine-like compounds. Several small
molecules were found to bind in the lysine-binding pocket of the kringle
1 domain of HGF/SF and its truncated splice variant NK1. We have defined the
binding mode of these compounds, explored their biological activity and we show
that selected fragments inhibit MET downstream signalling. Thus we demonstrate
that targeting the lysine-binding pocket of NK1 is an effective strategy
to generate MET receptor antagonists and we offer proof of concept that the
HGF/SF-MET interface may be successfully targeted with small molecules. These
studies have broad implications for the development of HGF/SF-MET therapeutics
and cancer treatment.
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
 |
 |
 |
|
Links
