4XLI

Crystal structure of Abl2/Arg kinase in complex with dasatinib


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.157 

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Literature

Structure of the ABL2/ARG kinase in complex with dasatinib.

Ha, B.H.Simpson, M.A.Koleske, A.J.Boggon, T.J.

(2015) Acta Crystallogr F Struct Biol Commun 71: 443-448

  • DOI: https://doi.org/10.1107/S2053230X15004793
  • Primary Citation of Related Structures:  
    4XLI

  • PubMed Abstract: 

    ABL2/ARG (ABL-related gene) belongs to the ABL (Abelson tyrosine-protein kinase) family of tyrosine kinases. ARG plays important roles in cell morphogenesis, motility, growth and survival, and many of these biological roles overlap with the cellular functions of the ABL kinase. Chronic myeloid leukemia (CML) is associated with constitutive ABL kinase activation resulting from fusion between parts of the breakpoint cluster region (BCR) and ABL1 genes. Similarly, fusion of the ETV6 (Tel) and ARG genes drives some forms of T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Dasatinib is a tyrosine kinase inhibitor used for the treatment of CML by inhibiting ABL, and while it also inhibits ARG, there is currently no structure of ARG in complex with dasatinib. Here, the co-crystal structure of the mouse ARG catalytic domain with dasatinib at 2.5 Å resolution is reported. Dasatinib-bound ARG is found in the DFG-in conformation although it is nonphosphorylated on the activation-loop tyrosine. In this structure the glycine-rich P-loop is found in a relatively open conformation compared with other known ABL family-inhibitor complex structures.


  • Organizational Affiliation

    Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Non-specific protein-tyrosine kinase
A, B
268Mus musculusMutation(s): 0 
Gene Names: Abl2
EC: 2.7.10.2
UniProt
Find proteins for Q4JIM5 (Mus musculus)
Explore Q4JIM5 
Go to UniProtKB:  Q4JIM5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ4JIM5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1N1
Query on 1N1

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
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
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1N1 BindingDB:  4XLI 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)
Binding MOAD:  4XLI Kd: 0.17 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.205 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.157 
  • Space Group: P 65
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 109.688α = 90
b = 109.688β = 90
c = 121.52γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
PHASERphasing
HKL-2000data reduction
Cootmodel building
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesR01GM100411

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-01
    Type: Initial release
  • Version 1.1: 2015-06-24
    Changes: Database references
  • Version 1.2: 2017-09-13
    Changes: Author supporting evidence, Derived calculations, Source and taxonomy
  • Version 1.3: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.4: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description