2HIW

Crystal Structure of Inactive Conformation Abl Kinase Catalytic Domain Complexed with Type II Inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.309 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.246 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

A general strategy for creating

Okram, B.Nagle, A.Adrian, F.J.Lee, C.Ren, P.Wang, X.Sim, T.Xie, Y.Wang, X.Xia, G.Spraggon, G.Warmuth, M.Liu, Y.Gray, N.S.

(2006) Chem Biol 13: 779-786

  • DOI: https://doi.org/10.1016/j.chembiol.2006.05.015
  • Primary Citation of Related Structures:  
    2HIW

  • PubMed Abstract: 

    Kinase inhibitors that bind to the ATP cleft can be broadly classified into two groups: those that bind exclusively to the ATP site with the kinase assuming a conformation otherwise conducive to phosphotransfer (type I), and those that exploit a hydrophobic site immediately adjacent to the ATP pocket made accessible by a conformational rearrangement of the activation loop (type II). To date, all type II inhibitors were discovered by using structure-activity-guided optimization strategies. Here, we describe a general pharmacophore model of type II inhibition that enables a rational "hybrid-design" approach whereby a 3-trifluoromethylbenzamide functionality is appended to four distinct type I scaffolds in order to convert them into their corresponding type II counterparts. We demonstrate that the designed compounds function as type II inhibitors by using biochemical and cellular kinase assays and by cocrystallography with Abl.


  • Organizational Affiliation

    Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, 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
287Homo 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
7MP
Query on 7MP

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
7-AMINO-1-METHYL-3-(2-METHYL-5-{[3-(TRIFLUOROMETHYL)BENZOYL]AMINO}PHENYL)-2-OXO-2,3-DIHYDROPYRIMIDO[4,5-D]PYRIMIDIN-1-IUM
C22 H18 F3 N6 O2
SQOIIWIQKKMCCG-UHFFFAOYSA-O
Binding Affinity Annotations 
IDSourceBinding Affinity
7MP Binding MOAD:  2HIW IC50: 8 (nM) from 1 assay(s)
PDBBind:  2HIW IC50: 8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.309 
  • R-Value Work: 0.243 
  • R-Value Observed: 0.246 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 41.485α = 90
b = 41.485β = 90
c = 332.602γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2006-08-22 
  • Deposition Author(s): Lee, C.

Revision History  (Full details and data files)

  • Version 1.0: 2006-08-22
    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