4KYA

Crystal structure of non-classical TS inhibitor 3 in complex with Toxoplasma gondii TS-DHFR


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.26 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.185 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections.

Zaware, N.Sharma, H.Yang, J.Devambatla, R.K.Queener, S.F.Anderson, K.S.Gangjee, A.

(2013) ACS Med Chem Lett 4: 1148-1151

  • DOI: https://doi.org/10.1021/ml400208v
  • Primary Citation of Related Structures:  
    4KY4, 4KYA

  • PubMed Abstract: 

    Infection by the parasite Toxoplasma gondii (tg) can lead to toxoplasmosis in immunocompromised patients such as organ transplant, cancer and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in T. gondii , and represents a potential target to combat T. gondii infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species and specificity is significantly more challenging. We discovered novel substituted-9 H -pyrimido[4,5- b ]indoles 1 - 3 with single-digit nanomolar K i for tgTS, two of which, 2 and 3 , are 28- and 122-fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data. These results show, for the very first time, that in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections.


  • Organizational Affiliation

    Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bifunctional dihydrofolate reductase-thymidylate synthase
A, B, C, D, E
A, B, C, D, E, F, G, H
566Toxoplasma gondiiMutation(s): 0 
EC: 1.5.1.3 (PDB Primary Data), 2.1.1.45 (PDB Primary Data)
UniProt
Find proteins for Q07422 (Toxoplasma gondii)
Explore Q07422 
Go to UniProtKB:  Q07422
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ07422
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

Download Ideal Coordinates CCD File 
BA [auth E]
FA [auth F]
JA [auth G]
L [auth A]
NA [auth H]
BA [auth E],
FA [auth F],
JA [auth G],
L [auth A],
NA [auth H],
P [auth B],
T [auth C],
X [auth D]
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
FOL
Query on FOL

Download Ideal Coordinates CCD File 
AA [auth E]
EA [auth F]
IA [auth G]
K [auth A]
MA [auth H]
AA [auth E],
EA [auth F],
IA [auth G],
K [auth A],
MA [auth H],
O [auth B],
S [auth C],
W [auth D]
FOLIC ACID
C19 H19 N7 O6
OVBPIULPVIDEAO-LBPRGKRZSA-N
1UG
Query on 1UG

Download Ideal Coordinates CCD File 
DA [auth F]
HA [auth G]
J [auth A]
LA [auth H]
N [auth B]
DA [auth F],
HA [auth G],
J [auth A],
LA [auth H],
N [auth B],
R [auth C],
V [auth D],
Z [auth E]
2-Amino-5-(1-naphthylsulfanyl)-3,9-dihydro-4H-pyrimido[4,5-b]indol-4-one
C20 H14 N4 O S
NSASWBYEPOLHJW-UHFFFAOYSA-N
UMP
Query on UMP

Download Ideal Coordinates CCD File 
CA [auth F]
GA [auth G]
I [auth A]
KA [auth H]
M [auth B]
CA [auth F],
GA [auth G],
I [auth A],
KA [auth H],
M [auth B],
Q [auth C],
U [auth D],
Y [auth E]
2'-DEOXYURIDINE 5'-MONOPHOSPHATE
C9 H13 N2 O8 P
JSRLJPSBLDHEIO-SHYZEUOFSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1UG BindingDB:  4KYA IC50: 36 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.26 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.182 
  • R-Value Observed: 0.185 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.531α = 90.07
b = 145.079β = 89.96
c = 176.614γ = 90.07
Software Package:
Software NamePurpose
PHENIXrefinement
SCALEPACKdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data collection
HKL-2000data reduction
HKL-2000data scaling
DENZOdata reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-08-06
    Type: Initial release
  • Version 1.1: 2017-08-09
    Changes: Data collection, Refinement description, Source and taxonomy
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.4: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description