2XX3

HUMAN THYMIDYLATE KINASE COMPLEXED WITH thymidine butenyl phosphonate monophosphate and ADP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 

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Literature

Novel Antiviral C5-Substituted Pyrimidine Acyclic Nucleoside Phosphonates Selected as Human Thymidylate Kinase Substrates.

Topalis, D.Pradere, U.Roy, V.Caillat, C.Azzouzi, A.Broggi, J.Snoeck, R.Andrei, G.Lin, J.Eriksson, S.Alexandre, J.A.C.El-Amri, C.Deville-Bonne, D.Meyer, P.Balzarini, J.Agrofoglio, L.A.

(2011) J Med Chem 54: 222

  • DOI: https://doi.org/10.1021/jm1011462
  • Primary Citation of Related Structures:  
    2XX3

  • PubMed Abstract: 

    Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies. They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases. New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase. Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate-cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovir. Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP. The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC(50) = 3 μM) and against varicella zoster virus in vitro (IC(50) = 0.19 μM), in contrast to the corresponding inactive (Z) derivatives. Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates.


  • Organizational Affiliation

    Groupe d'Enzymologie Moléculaire et Fonctionnelle, UR4-UPMC, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE KINASE232Homo sapiensMutation(s): 0 
EC: 2.7.4.9
UniProt & NIH Common Fund Data Resources
Find proteins for P23919 (Homo sapiens)
Explore P23919 
Go to UniProtKB:  P23919
PHAROS:  P23919
GTEx:  ENSG00000168393 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP23919
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 102.44α = 90
b = 38.32β = 123.07
c = 73.16γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
XDSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-12-07
    Type: Initial release