4E28

Structure of human thymidylate synthase in inactive conformation with a novel non-peptidic inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 

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Literature

Inhibitor of ovarian cancer cells growth by virtual screening: a new thiazole derivative targeting human thymidylate synthase.

Carosati, E., Tochowicz, A., Marverti, G., Guaitoli, G., Benedetti, P., Ferrari, S., Stroud, R.M., Finer-Moore, J., Luciani, R., Farina, D., Cruciani, G., Costi, M.P.

(2012) J Med Chem 55: 10272-10276

  • DOI: https://doi.org/10.1021/jm300850v
  • Primary Citation of Related Structures:  
    4E28

  • PubMed Abstract: 

    Human thymidylate synthase (hTS) was targeted through a virtual screening approach. The most optimal inhibitor identified, 2-{4-hydroxy-2-[(2-hydroxybenzylidene)hydrazono]-2,5-dihydrothiazol-5-yl}-N-(3-trifluoromethylphenyl)acetamide (5), showed a mixed-type inhibition pattern, with a K(i) of 1.3 μM and activity against ovarian cancer cell lines with the same potency as cisplatin. X-ray studies revealed that it binds the inactive enzyme conformation. This study is the first example of a nonpeptidic inhibitor that binds the inactive hTS and exhibits anticancer activity against ovarian cancer cells.

    • Organizational Affiliation: 

    Dipartimento di Chimica, Università degli Studi di Perugia , Via Elce di Sotto 10, 06123, Perugia, Italy.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Thymidylate synthase325Homo sapiensMutation(s): 0 
Gene Names: TYMS, TS, OK/SW-cl.29
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
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9MZ
Query on 9MZ
Download Ideal Coordinates CCD File 
E [auth A]2-{(5S)-2-[(2E)-2-(2-hydroxybenzylidene)hydrazinyl]-4-oxo-4,5-dihydro-1,3-thiazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide
C19 H15 F3 N4 O3 S
OBVIGUGYWMTZGZ-MQEPLNOPSA-N
0MZ
Query on 0MZ
Download Ideal Coordinates CCD File 
D [auth A]2-{(2Z,5S)-4-hydroxy-2-[(2E)-(2-hydroxybenzylidene)hydrazinylidene]-2,5-dihydro-1,3-thiazol-5-yl}-N-[3-(trifluoromethyl)phenyl]acetamide
C19 H15 F3 N4 O3 S
OBVIGUGYWMTZGZ-MQEPLNOPSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]		SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Modified Residues  1 Unique
IDChains TypeFormula2D DiagramParent
CME
Query on CME
A
L-PEPTIDE LINKINGC5 H11 N O3 S2CYS
Binding Affinity Annotations 
IDSourceBinding Affinity
0MZ Binding MOAD:  4E28 Ki: 1300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 95.747α = 90
b = 95.747β = 90
c = 82.407γ = 120
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
PHASERphasing
PHENIXrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-14
    Type: Initial release
  • Version 1.1: 2012-12-12
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description