4GAE

Crystal structure of plasmodium dxr in complex with a pyridine-containing inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Antimalarial and Structural Studies of Pyridine-containing Inhibitors of 1-Deoxyxylulose-5-phosphate Reductoisomerase.

Xue, J.Diao, J.Cai, G.Deng, L.Zheng, B.Yao, Y.Song, Y.

(2013) ACS Med Chem Lett 4: 278-282

  • DOI: https://doi.org/10.1021/ml300419r
  • Primary Citation of Related Structures:  
    4GAE

  • PubMed Abstract: 

    1-Deoxy- D -xylulose-5-phosphate reductoisomerase (DXR) in the non-mevalonate isoprene biosynthesis pathway is a target for developing antimalarial drugs. Fosmidomycin, a potent DXR inhibitor, showed safety as well as efficacy against P. falciparum malaria in clinical trials. Based on our previous quantitative structure activity relationship (QSAR) and crystallographic studies, several novel pyridine-containing fosmidomycin derivatives were designed, synthesized and found to be highly potent inhibitors of P. falciparum DXR ( Pf DXR) having K i values of 1.9 - 13 nM, with the best one being ~11× more active than fosmidomycin. These compounds also potently block the proliferation of multi-drug resistant P. falciparum with EC 50 values as low as 170 nM. A 2.3 Å crystal structure of Pf DXR in complex with one of the inhibitors is reported, showing the flexible loop of the protein undergoes conformational changes upon ligand binding and a hydrogen bond and favorable hydrophobic interactions between the pyridine group and Pf DXR account for the enhanced activity.


  • Organizational Affiliation

    Department of Pharmacology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
1-deoxy-D-xylulose 5-phosphate reductoisomerase, apicoplast
A, B
426Plasmodium falciparum HB3Mutation(s): 1 
Gene Names: DXR
EC: 1.1.1.267
UniProt
Find proteins for O96693 (Plasmodium falciparum (isolate HB3))
Explore O96693 
Go to UniProtKB:  O96693
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO96693
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

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

Download Ideal Coordinates CCD File 
E [auth A],
L [auth B]
[(1S)-3-[acetyl(hydroxy)amino]-1-(pyridin-4-yl)propyl]phosphonic acid
C10 H15 N2 O5 P
AMWIPWYKSYZXGB-JTQLQIEISA-N
FOB
Query on FOB

Download Ideal Coordinates CCD File 
D [auth A],
K [auth B]
[(1R)-3-[acetyl(hydroxy)amino]-1-(pyridin-4-yl)propyl]phosphonic acid
C10 H15 N2 O5 P
AMWIPWYKSYZXGB-SNVBAGLBSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
I [auth A],
Q [auth B],
R [auth B]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
H [auth A],
P [auth B]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
MN
Query on MN

Download Ideal Coordinates CCD File 
F [auth A],
M [auth B],
N [auth B],
O [auth B]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
FOQ Binding MOAD:  4GAE Ki: 13 (nM) from 1 assay(s)
FOB Binding MOAD:  4GAE Ki: 13 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.273 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.230 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.36α = 90
b = 77.28β = 91.5
c = 109.41γ = 90
Software Package:
Software NamePurpose
StructureStudiodata collection
PHASERphasing
CNSrefinement
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: 2013-02-06
    Type: Initial release
  • Version 1.1: 2013-07-10
    Changes: Database references
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description