1HW3

STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE SUGGESTS ADVANTAGES OF CHEMOTHERAPY WITH NONCOMPETITIVE INHIBITORS


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.203 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structure of human thymidylate synthase suggests advantages of chemotherapy with noncompetitive inhibitors.

Phan, J.Steadman, D.J.Koli, S.Ding, W.C.Minor, W.Dunlap, R.B.Berger, S.H.Lebioda, L.

(2001) J Biol Chem 276: 14170-14177

  • DOI: https://doi.org/10.1074/jbc.M009493200
  • Primary Citation of Related Structures:  
    1HW3, 1HW4

  • PubMed Abstract: 

    Thymidylate synthase (TS) is a major target in the chemotherapy of colorectal cancer and some other neoplasms. The emergence of resistance to the treatment is often related to the increased levels of TS in cancer cells, which have been linked to the elimination of TS binding to its own mRNA upon drug binding, a feedback regulatory mechanism, and/or to the increased stability to intracellular degradation of TS.drug complexes (versus unliganded TS). The active site loop of human TS (hTS) has a unique conformation resulted from a rotation by 180 degrees relative to its orientation in bacterial TSs. In this conformation, the enzyme must be inactive, because the catalytic cysteine is no longer positioned in the ligand-binding pocket. The ordered solvent structure obtained from high resolution crystallographic data (2.0 A) suggests that the inactive loop conformation promotes mRNA binding and intracellular degradation of the enzyme. This hypothesis is supported by fluorescence studies, which indicate that in solution both active and inactive forms of hTS are present. The binding of phosphate ion shifts the equilibrium toward the inactive conformation; subsequent dUMP binding reverses the equilibrium toward the active form. Thus, TS inhibition via stabilization of the inactive conformation should lead to less resistance than is observed with presently used drugs, which are analogs of its substrates, dUMP and CH(2)H(4)folate, and bind in the active site, promoting the active conformation. The presence of an extension at the N terminus of native hTS has no significant effect on kinetic properties or crystal structure.


  • Organizational Affiliation

    Departments of Chemistry and Biochemistry, University of South Carolina, Columbia 92908, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE SYNTHASE313Homo sapiensMutation(s): 4 
EC: 2.1.1.45
UniProt & NIH Common Fund Data Resources
Find proteins for P04818 (Homo sapiens)
Explore P04818 
Go to UniProtKB:  P04818
PHAROS:  P04818
GTEx:  ENSG00000176890 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04818
Sequence Annotations
Expand
  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.203 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.824α = 90
b = 95.824β = 90
c = 83.207γ = 120
Software Package:
Software NamePurpose
CNSrefinement
d*TREKdata reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-01-24
    Type: Initial release
  • Version 1.1: 2008-04-27
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2022-04-13
    Changes: Database references, Derived calculations, Structure summary