3PYY

Discovery and Characterization of a Cell-Permeable, Small-molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site.

Yang, J.Campobasso, N.Biju, M.P.Fisher, K.Pan, X.Q.Cottom, J.Galbraith, S.Ho, T.Zhang, H.Hong, X.Ward, P.Hofmann, G.Siegfried, B.Zappacosta, F.Washio, Y.Cao, P.Qu, J.Bertrand, S.Wang, D.Y.Head, M.S.Li, H.Moores, S.Lai, Z.Johanson, K.Burton, G.Erickson-Miller, C.Simpson, G.Tummino, P.Copeland, R.A.Oliff, A.

(2011) Chem Biol 18: 177-186

  • DOI: https://doi.org/10.1016/j.chembiol.2010.12.013
  • Primary Citation of Related Structures:  
    3PYY

  • PubMed Abstract: 

    c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.


  • Organizational Affiliation

    Oncology Research and Development, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. [email protected]


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
V-abl Abelson murine leukemia viral oncogene homolog 1 isoform b variant
A, B
298Homo sapiensMutation(s): 0 
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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
STI
Query on STI

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B]
4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE
C29 H31 N7 O
KTUFNOKKBVMGRW-UHFFFAOYSA-N
2PE
Query on 2PE

Download Ideal Coordinates CCD File 
I [auth B]NONAETHYLENE GLYCOL
C18 H38 O10
YZUUTMGDONTGTN-UHFFFAOYSA-N
3YY
Query on 3YY

Download Ideal Coordinates CCD File 
F [auth A],
K [auth B]
(5R)-5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]imidazolidine-2,4-dione
C18 H13 F N4 O2
MPQWYPLPWGUMJE-MRXNPFEDSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
G [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
J [auth B]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
STI BindingDB:  3PYY Ki: min: 13, max: 7000 (nM) from 5 assay(s)
Kd: min: 1, max: 1.00e+4 (nM) from 35 assay(s)
IC50: min: 1.1, max: 1.00e+4 (nM) from 68 assay(s)
EC50: min: 34, max: 1000 (nM) from 4 assay(s)
3YY PDBBind:  3PYY Kd: 137 (nM) from 1 assay(s)
BindingDB:  3PYY IC50: min: 251, max: 398 (nM) from 2 assay(s)
EC50: 794 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.204 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.189 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.391α = 90
b = 95.432β = 90
c = 115.502γ = 90
Software Package:
Software NamePurpose
MAR345dtbdata collection
PHASERphasing
PHENIXrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-03-09
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations, Structure summary