1TSL

L. CASEI THYMIDYLATE SYNTHASE WITH SPECIES SPECIFIC INHIBITOR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.163 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Structure-based design of inhibitors specific for bacterial thymidylate synthase.

Stout, T.J.Tondi, D.Rinaldi, M.Barlocco, D.Pecorari, P.Santi, D.V.Kuntz, I.D.Stroud, R.M.Shoichet, B.K.Costi, M.P.

(1999) Biochemistry 38: 1607-1617

  • DOI: https://doi.org/10.1021/bi9815896
  • Primary Citation of Related Structures:  
    1TSL, 1TSM

  • PubMed Abstract: 

    Thymidylate synthase is an attractive target for antiproliferative drug design because of its key role in the synthesis of DNA. As such, the enzyme has been widely targeted for anticancer applications. In principle, TS should also be a good target for drugs used to fight infectious disease. In practice, TS is highly conserved across species, and it has proven to be difficult to develop inhibitors that are selective for microbial TS enzymes over the human enzyme. Using the structure of TS from Lactobacillus casei in complex with the nonsubstrate analogue phenolphthalein, inhibitors were designed to take advantage of features of the bacterial enzyme that differ from those of the human enzyme. Upon synthesis and testing, these inhibitors were found to be up to 40-fold selective for the bacterial enzyme over the human enzyme. The crystal structures of two of these inhibitors in complex with TS suggested the design of further compounds. Subsequent synthesis and testing showed that these second-round compounds inhibit the bacterial enzyme at sub-micromolar concentrations, while the human enzyme was not inhibited at detectable levels (selectivities of 100-1000-fold or greater). Although these inhibitors share chemical similarities, X-ray crystal structures reveal that the analogues bind to the enzyme in substantially different orientations. Site-directed mutagenesis experiments suggest that the individual inhibitors may adopt multiple configurations in their complexes with TS.


  • Organizational Affiliation

    Department of Biochemistry, University of California, San Francisco 94143-0448, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THYMIDYLATE SYNTHASE316Lacticaseibacillus caseiMutation(s): 0 
EC: 2.1.1.45
UniProt
Find proteins for P00469 (Lacticaseibacillus casei)
Explore P00469 
Go to UniProtKB:  P00469
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00469
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A15
Query on A15

Download Ideal Coordinates CCD File 
C [auth A]3'-3"-DICHLOROPHENOL-1,8-3H-BENZO[DE]ISOCHROMEN-1-ONE
C24 H14 Cl2 O4
HCQHFJBXXMFZHF-UHFFFAOYSA-N
PO4
Query on PO4

Download Ideal Coordinates CCD File 
B [auth A]PHOSPHATE ION
O4 P
NBIIXXVUZAFLBC-UHFFFAOYSA-K
Binding Affinity Annotations 
IDSourceBinding Affinity
A15 PDBBind:  1TSL Ki: 700 (nM) from 1 assay(s)
BindingDB:  1TSL Ki: 700 (nM) from 1 assay(s)
Binding MOAD:  1TSL Ki: 700 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.163 
  • R-Value Observed: 0.163 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.3α = 90
b = 78.3β = 90
c = 243.2γ = 120
Software Package:
Software NamePurpose
X-PLORmodel building
X-PLORrefinement
MSCdata reduction
MSCdata scaling
X-PLORphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 1998-06-17
    Type: Initial release
  • Version 1.1: 2008-03-24
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Derived calculations, Version format compliance
  • Version 1.3: 2023-08-09
    Changes: Database references, Derived calculations, Other, Refinement description