7W7X

The crystal structure of human abl1 kinase domain in complex with ABL1-A11


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Cell-Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR-ABL Kinase.

Chen, P.Sun, J.Zhu, C.Tang, G.Wang, W.Xu, M.Xiang, M.Zhang, C.J.Zhang, Z.M.Gao, L.Yao, S.Q.

(2022) Angew Chem Int Ed Engl 61: e202203878-e202203878

  • DOI: https://doi.org/10.1002/anie.202203878
  • Primary Citation of Related Structures:  
    7W7X, 7W7Y

  • PubMed Abstract: 

    Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase. Our lead compounds showed high levels of selectivity in biochemical assays, exhibited nanomolar potency against endogenous ABL kinase in cellular assays, and were active against most drug-resistant ABL mutations. Among them, the salicylaldehyde-containing A5 is the first-ever reversible covalent ABL inhibitor that possessed time-dependent ABL inhibition with prolonged residence time and few cellular off-targets in K562 cells. Bioinformatics further suggested the generality of our strategy against the human kinome.


  • Organizational Affiliation

    School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase ABL1
A, B
272Homo sapiensMutation(s): 0 
Gene Names: ABL1
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
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8DW (Subject of Investigation/LOI)
Query on 8DW

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
5-[5-(dimethylcarbamoyl)pyridin-3-yl]-3-(5-fluorosulfonyloxy-2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine
C22 H19 F N4 O5 S
NPCQFNRTXVLCCU-UHFFFAOYSA-N
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.195 
  • R-Value Work: 0.168 
  • R-Value Observed: 0.169 
  • Space Group: P 2 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.408α = 90
b = 104.878β = 90
c = 132.906γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Cootmodel building
PHASERphasing
autoPROCdata processing
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2022-04-27
    Type: Initial release
  • Version 1.1: 2022-05-11
    Changes: Database references
  • Version 1.2: 2022-06-29
    Changes: Database references
  • Version 1.3: 2023-11-29
    Changes: Data collection, Refinement description