4CKR

Crystal structure of the human DDR1 kinase domain in complex with DDR1-IN-1


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a Potent and Selective Ddr1 Receptor Tyrosine Kinase Inhibitor.

Kim, H.Tan, L.Weisberg, E.L.Liu, F.Canning, P.Choi, H.G.Ezell, S.A.Wu, H.Zhao, Z.Wang, J.Mandinova, A.Griffin, J.D.Bullock, A.N.Liu, Q.Lee, S.W.Gray, N.S.

(2013) ACS Chem Biol 8: 2145

  • DOI: https://doi.org/10.1021/cb400430t
  • Primary Citation of Related Structures:  
    4CKR

  • PubMed Abstract: 

    The DDR1 receptor tyrosine kinase is activated by matrix collagens and has been implicated in numerous cellular functions such as proliferation, differentiation, adhesion, migration, and invasion. Here we report the discovery of a potent and selective DDR1 inhibitor, DDR1-IN-1, and present the 2.2 Å DDR1 co-crystal structure. DDR1-IN-1 binds to DDR1 in the 'DFG-out' conformation and inhibits DDR1 autophosphorylation in cells at submicromolar concentrations with good selectivity as assessed against a panel of 451 kinases measured using the KinomeScan technology. We identified a mutation in the hinge region of DDR1, G707A, that confers >20-fold resistance to the ability of DDR1-IN-1 to inhibit DDR1 autophosphorylation and can be used to establish what pharmacology is DDR1-dependent. A combinatorial screen of DDR1-IN-1 with a library of annotated kinase inhibitors revealed that inhibitors of PI3K and mTOR such as GSK2126458 potentiate the antiproliferative activity of DDR1-IN-1 in colorectal cancer cell lines. DDR1-IN-1 provides a useful pharmacological probe for DDR1-dependent signal transduction.


  • Organizational Affiliation

    Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School , Charlestown, Massachusetts 02129, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
EPITHELIAL DISCOIDIN DOMAIN-CONTAINING RECEPTOR 1315Homo 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
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
DI1 Binding MOAD:  4CKR IC50: 105 (nM) from 1 assay(s)
BindingDB:  4CKR IC50: min: 86, max: 105 (nM) from 2 assay(s)
EC50: 86 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.247 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.201 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 59.308α = 90
b = 59.308β = 90
c = 178.49γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-01-15
    Type: Initial release
  • Version 1.1: 2017-09-06
    Changes: Data collection
  • Version 1.2: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description