5T0L

Crystal structure of Toxoplasma gondii TS-DHFR complexed with NADPH, dUMP, PDDF and 5-(4-(3,4-dichlorophenyl)piperazin-1-yl)pyrimidine-2,4-diamine (TRC-15)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.13 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.253 
  • R-Value Observed: 0.254 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design.

Welsch, M.E.Zhou, J.Gao, Y.Yan, Y.Porter, G.Agnihotri, G.Li, Y.Lu, H.Chen, Z.Thomas, S.B.

(2016) ACS Med Chem Lett 7: 1124-1129

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00328
  • Primary Citation of Related Structures:  
    5T0L

  • PubMed Abstract: 

    Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC 50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC 50 < 10 μM and >2-fold selectivity favoring Toxoplasma gondii , further demonstrating the efficiency of our structure-based drug design approach.


  • Organizational Affiliation

    Turing Pharmaceuticals AG , Research & Development, 1177 Avenue of the Americas, 39th Floor, New York, New York 10036, 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
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 
D [auth A],
H [auth B]
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
CB3
Query on CB3

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B]
10-PROPARGYL-5,8-DIDEAZAFOLIC ACID
C24 H23 N5 O6
LTKHPMDRMUCUEB-IBGZPJMESA-N
73X
Query on 73X

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
5-[4-(3,4-dichlorophenyl)piperazin-1-yl]pyrimidine-2,4-diamine
C14 H16 Cl2 N6
YYBKNWXCJMWHIP-UHFFFAOYSA-N
UMP
Query on UMP

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
2'-DEOXYURIDINE 5'-MONOPHOSPHATE
C9 H13 N2 O8 P
JSRLJPSBLDHEIO-SHYZEUOFSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
73X BindingDB:  5T0L IC50: 17 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.13 Å
  • R-Value Free: 0.274 
  • R-Value Work: 0.253 
  • R-Value Observed: 0.254 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.277α = 90
b = 143.983β = 90
c = 170.214γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
Blu-Icedata collection
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-28
    Type: Initial release
  • Version 1.1: 2017-01-04
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Refinement description
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Refinement description