1NN1

Crystal structure of human thymidylate kinase with ddTMP and AppNHp


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.178 

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This is version 1.5 of the entry. See complete history


Literature

Structures of human thymidylate kinase in complex with prodrugs: implications for the structure-based design of novel compounds

Ostermann, N.Segura-Pena, D.Meier, C.Veit, T.Monnerjahn, M.Konrad, M.Lavie, A.

(2003) Biochemistry 42: 2568-2577

  • DOI: https://doi.org/10.1021/bi027302t
  • Primary Citation of Related Structures:  
    1NMX, 1NMY, 1NMZ, 1NN0, 1NN1, 1NN3, 1NN5

  • PubMed Abstract: 

    Nucleoside analogue prodrugs are dependent on efficient intracellular stepwise phosphorylation to their triphosphate form to become therapeutically active. In many cases it is this activation pathway that largely determines the efficacy of the drug. To gain further understanding of the determinants for efficient conversion by the enzyme thymidylate kinase (TMPK) of clinically important thymidine monophosphate analogues to the corresponding diphosphates, we solved the crystal structures of the enzyme, with either ADP or the ATP analogue AppNHp at the phosphoryl donor site, in complex with TMP, AZTMP (previous work), NH2TMP, d4TMP, ddTMP, and FLTMP (this work) at the phosphoryl acceptor site. In conjunction with steady-state kinetic data, our structures shed light on the effect of 3'-substitutions in the nucleoside monophosphate (NMP) sugar moiety on the catalytic rate. We observe a direct correlation between the rate of phosphorylation of an NMP and its ability to induce a closing of the enzyme's phosphate-binding loop (P-loop). Our results show the drastic effects that slight modifications of the substrates exert on the enzyme's conformation and, hence, activity and suggest the type of substitutions that are compatible with efficient phosphorylation by TMPK.


  • Organizational Affiliation

    Department of Physical Biochemistry, Max Planck Institute for Molecular Physiology, Otto-Hahn-Strasse 11, 44227 Dortmund, Germany.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
similar to THYMIDYLATE KINASE (DTMP KINASE)215Homo sapiensMutation(s): 1 
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: 1.90 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.178 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 101.426α = 90
b = 101.426β = 90
c = 49.322γ = 90
Software Package:
Software NamePurpose
MAR345data collection
XDSdata reduction
REFMACrefinement
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: 2003-03-18
    Type: Initial release
  • Version 1.1: 2008-04-29
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2021-10-27
    Changes: Database references, Derived calculations
  • Version 1.5: 2024-02-14
    Changes: Data collection