4DDR

Human dihydrofolate reductase complexed with NADPH and P218


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.205 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target

Yuthavong, Y.Tarnchompoo, B.Vilaivan, T.Chitnumsub, P.Kamchonwongpaisan, S.Charman, S.A.McLennan, D.N.White, K.L.Vivas, L.Bongard, E.Thongphanchang, C.Taweechai, S.Vanichtanankul, J.Rattanajak, R.Arwon, U.Fantauzzi, P.Yuvaniyama, J.Charman, W.N.Matthews, D.

(2012) Proc Natl Acad Sci U S A 109: 16823-16828

  • DOI: https://doi.org/10.1073/pnas.1204556109
  • Primary Citation of Related Structures:  
    4DDR, 4DP3, 4DPD, 4DPH

  • PubMed Abstract: 

    Malarial dihydrofolate reductase (DHFR) is the target of antifolate antimalarial drugs such as pyrimethamine and cycloguanil, the clinical efficacy of which have been compromised by resistance arising through mutations at various sites on the enzyme. Here, we describe the use of cocrystal structures with inhibitors and substrates, along with efficacy and pharmacokinetic profiling for the design, characterization, and preclinical development of a selective, highly efficacious, and orally available antimalarial drug candidate that potently inhibits both wild-type and clinically relevant mutated forms of Plasmodium falciparum (Pf) DHFR. Important structural characteristics of P218 include pyrimidine side-chain flexibility and a carboxylate group that makes charge-mediated hydrogen bonds with conserved Arg122 (PfDHFR-TS amino acid numbering). An analogous interaction of P218 with human DHFR is disfavored because of three species-dependent amino acid substitutions in the vicinity of the conserved Arg. Thus, P218 binds to the active site of PfDHFR in a substantially different fashion from the human enzyme, which is the basis for its high selectivity. Unlike pyrimethamine, P218 binds both wild-type and mutant PfDHFR in a slow-on/slow-off tight-binding mode, which prolongs the target residence time. P218, when bound to PfDHFR-TS, resides almost entirely within the envelope mapped out by the dihydrofolate substrate, which may make it less susceptible to resistance mutations. The high in vivo efficacy in a SCID mouse model of P. falciparum malaria, good oral bioavailability, favorable enzyme selectivity, and good safety characteristics of P218 make it a potential candidate for further development.


  • Organizational Affiliation

    BIOTEC, National Science and Technology Development Agency, Thailand Science Park, Pathumthani 12120, Thailand. yongyuth@biotec.or.th


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductase186Homo sapiensMutation(s): 0 
Gene Names: DHFR
EC: 1.5.1.3
UniProt & NIH Common Fund Data Resources
Find proteins for P00374 (Homo sapiens)
Explore P00374 
Go to UniProtKB:  P00374
PHAROS:  P00374
GTEx:  ENSG00000228716 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00374
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

Download Ideal Coordinates CCD File 
B [auth A]NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
MMV
Query on MMV

Download Ideal Coordinates CCD File 
C [auth A]3-(2-{3-[(2,4-diamino-6-ethylpyrimidin-5-yl)oxy]propoxy}phenyl)propanoic acid
C18 H24 N4 O4
VDGXZSSDCDPCRF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
MMV Binding MOAD:  4DDR Ki: 2841 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.05 Å
  • R-Value Free: 0.249 
  • R-Value Work: 0.205 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.285α = 90
b = 85.285β = 90
c = 77.131γ = 120
Software Package:
Software NamePurpose
d*TREKdata scaling
d*TREKdata reduction
MOLREPphasing
CNSrefinement
PDB_EXTRACTdata extraction
CrystalCleardata collection
CrystalCleardata reduction
CrystalCleardata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-11-14
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description