2G1T

A Src-like Inactive Conformation in the Abl Tyrosine Kinase Domain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 

Starting Model: experimental
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This is version 1.3 of the entry. See complete history


Literature

A SRC-like inactive conformation in the abl tyrosine kinase domain.

Levinson, N.M.Kuchment, O.Shen, K.Young, M.A.Koldobskiy, M.Karplus, M.Cole, P.A.Kuriyan, J.

(2006) PLoS Biol 4: 753-767

  • DOI: https://doi.org/10.1371/journal.pbio.0040144
  • Primary Citation of Related Structures:  
    2G1T, 2G2F, 2G2H, 2G2I

  • PubMed Abstract: 

    The improper activation of the Abl tyrosine kinase results in chronic myeloid leukemia (CML). The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly (DFG) motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat CML. The DFG motif is not flipped in crystal structures of inactive forms of the closely related Src kinases, and imatinib does not inhibit c-Src. We present a structure of the kinase domain of Abl, determined in complex with an ATP-peptide conjugate, in which the protein adopts an inactive conformation that resembles closely that of the Src kinases. An interesting aspect of the Src-like inactive structure, suggested by molecular dynamics simulations and additional crystal structures, is the presence of features that might facilitate the flip of the DFG motif by providing room for the phenylalanine to move and by coordinating the aspartate side chain as it leaves the active site. One class of mutations in BCR-Abl that confers resistance to imatinib appears more likely to destabilize the inactive Src-like conformation than the active or imatinib-bound conformations. Our results suggest that interconversion between distinctly different inactive conformations is a characteristic feature of the Abl kinase domain.


  • Organizational Affiliation

    Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Proto-oncogene tyrosine-protein kinase ABL1
A, B, C, D
287Homo sapiensMutation(s): 0 
Gene Names: ABL1ABLJTK7
EC: 2.7.1.112
UniProt & NIH Common Fund Data Resources
Find proteins for P00519 (Homo sapiens)
Explore P00519 
Go to UniProtKB:  P00519
PHAROS:  P00519
GTEx:  ENSG00000097007 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00519
Sequence Annotations
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  • Reference Sequence

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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
ATP-Peptide Conjugate
E, F, G, H
13N/AMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.219 
  • R-Value Observed: 0.221 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.586α = 90
b = 78.44β = 90.11
c = 141.609γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
PHASERphasing
CNSrefinement
HKL-2000data reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-05-23
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description