2QOH

Crystal Structure of Abl kinase bound with PPY-A


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.214 

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This is version 1.2 of the entry. See complete history


Literature

Crystal Structure of the T315I Mutant of Abl Kinase

Zhou, T.Parillon, L.Li, F.Wang, Y.Keats, J.Lamore, S.Xu, Q.Shakespeare, W.Dalgarno, D.Zhu, X.

(2007) Chem Biol Drug Des 70: 171-181

  • DOI: https://doi.org/10.1111/j.1747-0285.2007.00556.x
  • Primary Citation of Related Structures:  
    2QOH, 2Z60

  • PubMed Abstract: 

    Imatinib (Gleevec) is currently the frontline therapy for chronic myeloid leukemia (CML), a disease characterized by the presence of a constitutively activated chimeric tyrosine kinase protein Bcr-AbI. However, drug resistance often occurs at later stages of the disease, principally because of the occurrence of mutations in the kinase domain. Second generation Bcr-AbI inhibitors, such as dasatinib and nilotinib are capable of inhibiting many imatinib-resistant forms of the kinase but not the form in which threonine is mutated to isoleucine at the gatekeeper position (T315I). In this study, we present the crystal structure of the kinase domain of the c-AbI T315I mutant, as well as the wild-type form, in complex with a pyrrolopyridine inhibitor, PPY-A. The side chain of Ile315 is accommodated in the AbI T315I mutant structure without large conformational changes proximal to the site of mutation. In contrast to other inhibitors, such as imatinib and dasatinib, PPY-A does not occupy the hydrophobic pocket behind the gatekeeper residue. This binding mode, coupled with augmented contacts with the glycine-rich loop, appears to be critical for its ability to override the T315I mutation. The data presented here may provide structural guidance for the design of clinically useful inhibitors of Bcr-AbI T315I.


  • Organizational Affiliation

    ARIAD Pharmaceuticals Inc, 26 Landsdowne St., Cambridge, MA 02139, 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
288Mus musculusMutation(s): 0 
EC: 2.7.10.2
UniProt
Find proteins for P00520 (Mus musculus)
Explore P00520 
Go to UniProtKB:  P00520
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00520
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
P3Y
Query on P3Y

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
5-[3-(2-METHOXYPHENYL)-1H-PYRROLO[2,3-B]PYRIDIN-5-YL]-N,N-DIMETHYLPYRIDINE-3-CARBOXAMIDE
C22 H20 N4 O2
GYQRHHQPEMOLKH-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
P3Y BindingDB:  2QOH Ki: 20 (nM) from 1 assay(s)
IC50: min: 9, max: 20 (nM) from 2 assay(s)
PDBBind:  2QOH IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.255 
  • R-Value Work: 0.214 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.008α = 90
b = 59.128β = 118.39
c = 75.938γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2007-09-18
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-10-25
    Changes: Data collection, Database references, Derived calculations, Refinement description