4Q1B

Human dCK C4S-S74E mutant in complex with UDP and the inhibitor 7 {N-(2-(3-(4-(((4,6-diaminopyrimidin-2-yl)thio)methyl)-5-propylthiazol-2-yl)phenoxy)ethyl)methanesulfonamide}


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-guided development of deoxycytidine kinase inhibitors with nanomolar affinity and improved metabolic stability.

Nomme, J.Li, Z.Gipson, R.M.Wang, J.Armijo, A.L.Le, T.Poddar, S.Smith, T.Santarsiero, B.D.Nguyen, H.A.Czernin, J.Alexandrova, A.N.Jung, M.E.Radu, C.G.Lavie, A.

(2014) J Med Chem 57: 9480-9494

  • DOI: https://doi.org/10.1021/jm501124j
  • Primary Citation of Related Structures:  
    4Q18, 4Q19, 4Q1A, 4Q1B, 4Q1C, 4Q1D, 4Q1E, 4Q1F

  • PubMed Abstract: 

    Recently, we have shown that small molecule dCK inhibitors in combination with pharmacological perturbations of de novo dNTP biosynthetic pathways could eliminate acute lymphoblastic leukemia cells in animal models. However, our previous lead compound had a short half-life in vivo. Therefore, we set out to develop dCK inhibitors with favorable pharmacokinetic properties. We delineated the sites of the inhibitor for modification, guided by crystal structures of dCK in complex with the lead compound and with derivatives. Crystal structure of the complex between dCK and the racemic mixture of our new lead compound indicated that the R-isomer is responsible for kinase inhibition. This was corroborated by kinetic analysis of the purified enantiomers, which showed that the R-isomer has >60-fold higher affinity than the S-isomer for dCK. This new lead compound has significantly improved metabolic stability, making it a prime candidate for dCK-inhibitor based therapies against hematological malignancies and, potentially, other cancers.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Genetics, and ‡Center for Pharmaceutical Biotechnology, University of Illinois at Chicago , Chicago, Illinois 60607, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Deoxycytidine kinase
A, B
280Homo sapiensMutation(s): 5 
Gene Names: DCK
EC: 2.7.1.74
UniProt & NIH Common Fund Data Resources
Find proteins for P27707 (Homo sapiens)
Explore P27707 
Go to UniProtKB:  P27707
PHAROS:  P27707
GTEx:  ENSG00000156136 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27707
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
2Y0 BindingDB:  4Q1B Ki: 1.9 (nM) from 1 assay(s)
IC50: min: 12, max: 17 (nM) from 2 assay(s)
Binding MOAD:  4Q1B Ki: 1.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.177 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.968α = 90
b = 68.968β = 90
c = 121.944γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
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: 2015-02-18
    Type: Initial release
  • Version 1.1: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description