5CP9

The structure of the NK1 fragment of HGF/SF complexed with MB605


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

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.

Sigurdardottir, A.G.Winter, A.Sobkowicz, A.Fragai, M.Chirgadze, D.Ascher, D.B.Blundell, T.L.Gherardi, E.

(2015) Chem Sci 6: 6147-6157

  • DOI: https://doi.org/10.1039/c5sc02155c
  • Primary Citation of Related Structures:  
    5COE, 5CP9, 5CS1, 5CS3, 5CS5, 5CS9, 5CSQ, 5CT1, 5CT2, 5CT3

  • PubMed 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.


  • Organizational Affiliation

    Department of Biochemistry , University of Cambridge , 80 Tennis Court Road , Cambridge , CB2 1GA , UK . Email: tlb20@cam.ac.uk ; Email: sigurdar@mrc-lmb.cam.ac.uk.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor
A, B
183Homo sapiensMutation(s): 1 
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
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6O5
Query on 6O5

Download Ideal Coordinates CCD File 
C [auth B]3-(furan-2-yl)propanoic acid
C7 H8 O3
XLTJXJJMUFDQEZ-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth B]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.227 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.196 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.387α = 90
b = 63.649β = 95.24
c = 57.198γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-12
    Type: Initial release
  • Version 1.1: 2016-10-26
    Changes: Database references
  • Version 1.2: 2018-08-29
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Refinement description