3ZOS

Structure of the DDR1 kinase domain in complex with ponatinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history


Literature

Structural Mechanisms Determining Inhibition of the Collagen Receptor Ddr1 by Selective and Multi-Targeted Type II Kinase Inhibitors

Canning, P.Elkins, J.M.Goubin, S.Mahajan, P.Bradley, A.Coutandin, D.von Delft, F.Arrowsmith, C.H.Edwards, A.M.Bountra, C.Bullock, A.

(2014) J Mol Biol 426: 2457

  • DOI: https://doi.org/10.1016/j.jmb.2014.04.014
  • Primary Citation of Related Structures:  
    3ZOS, 4BKJ

  • PubMed Abstract: 

    The discoidin domain receptors (DDRs), DDR1 and DDR2, form a unique subfamily of receptor tyrosine kinases that are activated by the binding of triple-helical collagen. Excessive signaling by DDR1 and DDR2 has been linked to the progression of various human diseases, including fibrosis, atherosclerosis and cancer. We report the inhibition of these unusual receptor tyrosine kinases by the multi-targeted cancer drugs imatinib and ponatinib, as well as the selective type II inhibitor DDR1-IN-1. Ponatinib is identified as the more potent molecule, which inhibits DDR1 and DDR2 with an IC50 of 9nM. Co-crystal structures of human DDR1 reveal a DFG-out conformation (DFG, Asp-Phe-Gly) of the kinase domain that is stabilized by an unusual salt bridge between the activation loop and αD helix. Differences to Abelson kinase (ABL) are observed in the DDR1 P-loop, where a β-hairpin replaces the cage-like structure of ABL. P-loop residues in DDR1 that confer drug resistance in ABL are therefore accommodated outside the ATP pocket. Whereas imatinib and ponatinib bind potently to both the DDR and ABL kinases, the hydrophobic interactions of the ABL P-loop appear poorly satisfied by DDR1-IN-1 suggesting a structural basis for its DDR1 selectivity. Such inhibitors may have applications in clinical indications of DDR1 and DDR2 overexpression or mutation, including lung cancer.


  • Organizational Affiliation

    Structural Genomics Consortium, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
EPITHELIAL DISCOIDIN DOMAIN-CONTAINING RECEPTOR 1
A, B
315Homo sapiensMutation(s): 0 
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q08345 (Homo sapiens)
Explore Q08345 
Go to UniProtKB:  Q08345
PHAROS:  Q08345
GTEx:  ENSG00000204580 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08345
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.92 Å
  • R-Value Free: 0.234 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.208 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.951α = 90
b = 61.733β = 104.4
c = 80.193γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-05-01
    Type: Initial release
  • Version 1.1: 2014-04-23
    Changes: Database references
  • Version 1.2: 2014-05-07
    Changes: Database references
  • Version 1.3: 2014-06-18
    Changes: Database references
  • Version 1.4: 2018-01-24
    Changes: Database references
  • Version 1.5: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Structure summary