4JLM

Human dCK C4S-S74E mutant in complex with UDP and the F2.3.1 inhibitor (2-[({5-ETHYL-2-[3-(2-FLUOROETHOXY)-4-METHOXYPHENYL]-1,3-THIAZOL-4-YL}METHYL)SULFANYL]PYRIMIDINE-4,6-DIAMINE)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.171 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structural characterization of new deoxycytidine kinase inhibitors rationalizes the affinity-determining moieties of the molecules.

Nomme, J.Murphy, J.M.Su, Y.Sansone, N.D.Armijo, A.L.Olson, S.T.Radu, C.Lavie, A.

(2014) Acta Crystallogr D Biol Crystallogr 70: 68-78

  • DOI: https://doi.org/10.1107/S1399004713025030
  • Primary Citation of Related Structures:  
    4JLJ, 4JLM, 4JLN

  • PubMed Abstract: 

    Deoxycytidine kinase (dCK) is a key enzyme in the nucleoside salvage pathway that is also required for the activation of several anticancer and antiviral nucleoside analog prodrugs. Additionally, dCK has been implicated in immune disorders and has been found to be overexpressed in several cancers. To allow the probing and modulation of dCK activity, a new class of small-molecule inhibitors of the enzyme were developed. Here, the structural characterization of four of these inhibitors in complex with human dCK is presented. The structures reveal that the compounds occupy the nucleoside-binding site and bind to the open form of dCK. Surprisingly, a slight variation in the nature of the substituent at the 5-position of the thiazole ring governs whether the active site of the enzyme is occupied by one or two inhibitor molecules. Moreover, this substituent plays a critical role in determining the affinity, improving it from >700 to 1.5 nM in the best binder. These structures lay the groundwork for future modifications that would result in even tighter binding and the correct placement of moieties that confer favorable pharmacodynamics and pharmacokinetic properties.


  • Organizational Affiliation

    Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA.


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
1NN Binding MOAD:  4JLM Ki: 6.1 (nM) from 1 assay(s)
BindingDB:  4JLM IC50: min: 7, max: 30 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.171 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.516α = 90
b = 68.516β = 90
c = 121.285γ = 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: 2014-01-22
    Type: Initial release
  • Version 1.1: 2014-02-19
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations