3LQ8

Structure of the kinase domain of c-Met bound to XL880 (GSK1363089)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases.

Qian, F.Engst, S.Yamaguchi, K.Yu, P.Won, K.A.Mock, L.Lou, T.Tan, J.Li, C.Tam, D.Lougheed, J.Yakes, F.M.Bentzien, F.Xu, W.Zaks, T.Wooster, R.Greshock, J.Joly, A.H.

(2009) Cancer Res 69: 8009-8016

  • DOI: https://doi.org/10.1158/0008-5472.CAN-08-4889
  • Primary Citation of Related Structures:  
    3LQ8

  • PubMed Abstract: 

    The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor beta, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addition, EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors.


  • Organizational Affiliation

    Exelixis, Inc, South San Francisco, California 94083, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Hepatocyte growth factor receptor302Homo 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
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
88Z
Query on 88Z

Download Ideal Coordinates CCD File 
B [auth A]N-(3-fluoro-4-{[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
C34 H34 F2 N4 O6
CXQHYVUVSFXTMY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
88Z BindingDB:  3LQ8 IC50: min: 0.4, max: 214 (nM) from 22 assay(s)
PDBBind:  3LQ8 IC50: 0.4 (nM) from 1 assay(s)
Binding MOAD:  3LQ8 IC50: 0.4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.252 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.925α = 90
b = 43.017β = 91.61
c = 89.618γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-05-19
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations