3IK1

Lactobacillus casei Thymidylate Synthase in Ternary Complex with dUMP and the Phtalimidic Derivative 20C


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.215 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Identification of the binding modes of N-phenylphthalimides inhibiting bacterial thymidylate synthase through X-ray crystallography screening

Mangani, S.Cancian, L.Leone, R.Pozzi, C.Lazzari, S.Luciani, R.Ferrari, S.Costi, M.P.

(2011) J Med Chem 54: 5454-5467

  • DOI: https://doi.org/10.1021/jm2005018
  • Primary Citation of Related Structures:  
    3BNZ, 3BYX, 3BZ0, 3C06, 3C0A, 3IJZ, 3IK0, 3IK1

  • PubMed Abstract: 

    To identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both bacterial and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes of the inhibitor, which prevented a classical structure-based drug design approach. To overcome this issue, we synthesized two phthalimidic libraries that were tested against TS enzymes and then we performed X-ray crystallographic screening of the active compounds. Compounds 6A, 8A, and 12A showed 40-fold higher affinity for bacterial TS than human TS. The X-ray crystallographic screening characterized the binding mode of six inhibitors in complexes with LcTS. Of these, 20A, 23A, and 24A showed a common unique binding mode, whereas 8A showed a different, unique binding mode. A comparative analysis of the LcTS X-ray complexes that were obtained with the pathogenic TS enabled the selection of compounds 8A and 23A as specific compounds and starting points to be exploited for the specific inhibition of pathogen enzymes.


  • Organizational Affiliation

    Dipartimento di Scienze Farmaceutiche, Università degli Studi di Modena e Reggio Emilia, Modena, Italy. mangani@unisi.it


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
UMP
Query on UMP

Download Ideal Coordinates CCD File 
C [auth A]2'-DEOXYURIDINE 5'-MONOPHOSPHATE
C9 H13 N2 O8 P
JSRLJPSBLDHEIO-SHYZEUOFSA-N
20C
Query on 20C

Download Ideal Coordinates CCD File 
B [auth A]2-hydroxy-4-(4-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzoic acid
C16 H11 N O5
SPKSOWKQTVDRTK-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
20C BindingDB:  3IK1 Ki: 1.40e+4 (nM) from 1 assay(s)
PDBBind:  3IK1 Ki: 1.40e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.271 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.215 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.985α = 90
b = 77.985β = 90
c = 224.718γ = 120
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-08-11
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2013-07-24
    Changes: Database references
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description