4XEY

Crystal structure of an SH2-kinase domain construct of c-Abl tyrosine kinase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.89 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.232 

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This is version 1.3 of the entry. See complete history


Literature

Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity.

Lorenz, S.Deng, P.Hantschel, O.Superti-Furga, G.Kuriyan, J.

(2015) Biochem J 468: 283-291

  • DOI: https://doi.org/10.1042/BJ20141492
  • Primary Citation of Related Structures:  
    4XEY

  • PubMed Abstract: 

    Constitutive activation of the non-receptor tyrosine kinase c-Abl (cellular Abelson tyrosine protein kinase 1, Abl1) in the Bcr (breakpoint cluster region)-Abl1 fusion oncoprotein is the molecular cause of chronic myeloid leukaemia (CML). Recent studies have indicated that an interaction between the SH2 (Src-homology 2) domain and the N-lobe (N-terminal lobe) of the c-Abl kinase domain (KD) has a critical role in leukaemogenesis [Grebien et al. (2011) Cell 147, 306-319; Sherbenou et al. (2010) Blood 116, 3278-3285]. To dissect the structural basis of this phenomenon, we studied c-Abl constructs comprising the SH2 and KDs in vitro. We present a crystal structure of an SH2-KD construct bound to dasatinib, which contains the relevant interface between the SH2 domain and the N-lobe of the KD. We show that the presence of the SH2 domain enhances kinase activity moderately and that this effect depends on contacts in the SH2/N-lobe interface and is abrogated by specific mutations. Consistently, formation of the interface decreases slightly the association rate of imatinib with the KD. That the effects are small compared with the dramatic in vivo consequences suggests an important function of the SH2-N-lobe interaction might be to help disassemble the auto-inhibited conformation of c-Abl and promote processive phosphorylation, rather than substantially stimulate kinase activity.


  • Organizational Affiliation

    *California Institute for Quantitative Biosciences, University of California at Berkeley, Berkeley, CA 94720, U.S.A.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ABL1A [auth B],
B [auth A]
408Homo sapiensMutation(s): 0 
Gene Names: ABL1ABLJTK7
EC: 2.7.10.2
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
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1N1
Query on 1N1

Download Ideal Coordinates CCD File 
C [auth B],
D [auth A]
N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE
C22 H26 Cl N7 O2 S
ZBNZXTGUTAYRHI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1N1 BindingDB:  4XEY Kd: min: 0.02, max: 120 (nM) from 28 assay(s)
IC50: min: 0.14, max: 1000 (nM) from 19 assay(s)
EC50: 0.04 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.89 Å
  • R-Value Free: 0.259 
  • R-Value Work: 0.231 
  • R-Value Observed: 0.232 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 114.118α = 90
b = 125.449β = 90
c = 56.232γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Leukemia & Lymphoma SocietyUnited States7393-06

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-01
    Type: Initial release
  • Version 1.1: 2015-06-03
    Changes: Database references
  • Version 1.2: 2017-09-27
    Changes: Author supporting evidence, Database references, Derived calculations, Source and taxonomy
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Refinement description