3VRY

Crystal structure of HCK complexed with a pyrrolo-pyrimidine inhibitor 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-cyclopentane


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.229 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

A Pyrrolo-Pyrimidine Derivative Targets Human Primary AML Stem Cells in Vivo

Saito, Y.Yuki, H.Kuratani, M.Hashizume, Y.Takagi, S.Honma, T.Tanaka, A.Shirouzu, M.Mikuni, J.Handa, N.Ogahara, I.Sone, A.Najima, Y.Tomabechi, Y.Wakiyama, M.Uchida, N.Tomizawa-Murasawa, M.Kaneko, A.Tanaka, S.Suzuki, N.Kajita, H.Aoki, Y.Ohara, O.Shultz, L.D.Fukami, T.Goto, T.Taniguchi, S.Yokoyama, S.Ishikawa, F.

(2013) Sci Transl Med 5: 181ra52-181ra52

  • DOI: https://doi.org/10.1126/scitranslmed.3004387
  • Primary Citation of Related Structures:  
    3VRY, 3VRZ, 3VS0, 3VS1, 3VS2, 3VS3, 3VS4, 3VS5, 3VS6, 3VS7

  • PubMed Abstract: 

    Leukemia stem cells (LSCs) that survive conventional chemotherapy are thought to contribute to disease relapse, leading to poor long-term outcomes for patients with acute myeloid leukemia (AML). We previously identified a Src-family kinase (SFK) member, hematopoietic cell kinase (HCK), as a molecular target that is highly differentially expressed in human primary LSCs compared with human normal hematopoietic stem cells (HSCs). We performed a large-scale chemical library screen that integrated a high-throughput enzyme inhibition assay, in silico binding prediction, and crystal structure determination and found a candidate HCK inhibitor, RK-20449, a pyrrolo-pyrimidine derivative with an enzymatic IC50 (half maximal inhibitory concentration) in the subnanomolar range. A crystal structure revealed that RK-20449 bound the activation pocket of HCK. In vivo administration of RK-20449 to nonobese diabetic (NOD)/severe combined immunodeficient (SCID)/IL2rg(null) mice engrafted with highly aggressive therapy-resistant AML significantly reduced human LSC and non-stem AML burden. By eliminating chemotherapy-resistant LSCs, RK-20449 may help to prevent relapse and lead to improved patient outcomes in AML.


  • Organizational Affiliation

    Laboratory for Human Disease Models, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Tyrosine-protein kinase HCK
A, B
454Homo sapiensMutation(s): 3 
Gene Names: HCK
EC: 2.7.10.2
UniProt & NIH Common Fund Data Resources
Find proteins for P08631 (Homo sapiens)
Explore P08631 
Go to UniProtKB:  P08631
PHAROS:  P08631
GTEx:  ENSG00000101336 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08631
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
PTR
Query on PTR
A, B
L-PEPTIDE LINKINGC9 H12 N O6 PTYR
Binding Affinity Annotations 
IDSourceBinding Affinity
B43 PDBBind:  3VRY IC50: 7.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.48 Å
  • R-Value Free: 0.281 
  • R-Value Work: 0.226 
  • R-Value Observed: 0.229 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.59α = 90
b = 73.88β = 95.84
c = 178.47γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
XDSdata 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: 2013-05-01
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.2: 2023-12-06
    Changes: Data collection