4Y6R

Structure of Plasmodium falciparum DXR in complex with a beta-substituted fosmidomycin analogue, RC137, and manganese


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Synthesis and Bioactivity of beta-Substituted Fosmidomycin Analogues Targeting 1-Deoxy-d-xylulose-5-phosphate Reductoisomerase.

Chofor, R.Sooriyaarachchi, S.Risseeuw, M.D.Bergfors, T.Pouyez, J.Johny, C.Haymond, A.Everaert, A.Dowd, C.S.Maes, L.Coenye, T.Alex, A.Couch, R.D.Jones, T.A.Wouters, J.Mowbray, S.L.Van Calenbergh, S.

(2015) J Med Chem 58: 2988-3001

  • DOI: https://doi.org/10.1021/jm5014264
  • Primary Citation of Related Structures:  
    4Y67, 4Y6P, 4Y6R, 4Y6S

  • PubMed Abstract: 

    Blocking the 2-C-methyl-d-erythrithol-4-phosphate (MEP) pathway for isoprenoid biosynthesis offers interesting prospects for inhibiting Plasmodium or Mycobacterium spp. growth. Fosmidomycin (1) and its homologue FR900098 (2) potently inhibit 1-deoxy-d-xylulose-5-phosphate reductoisomerase (Dxr), a key enzyme in this pathway. Here we introduced aryl or aralkyl substituents at the β-position of the hydroxamate analogue of 2. While direct addition of a β-aryl moiety resulted in poor inhibition, longer linkers between the carbon backbone and the phenyl ring were generally associated with better binding to the enzymes. X-ray structures of the parasite Dxr-inhibitor complexes show that the "longer" compounds generate a substantially different flap structure, in which a key tryptophan residue is displaced, and the aromatic group of the ligand lies between the tryptophan and the hydroxamate's methyl group. Although the most promising new Dxr inhibitors lack activity against Escherichia coli and Mycobacterium smegmatis, they proved to be highly potent inhibitors of Plasmodium falciparum in vitro growth.


  • Organizational Affiliation

    †Laboratory for Medicinal Chemistry (FFW), Universiteit Gent, Ottergemsesteenweg 460, B-9000 Gent, Belgium.


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
422Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: DXRPF14_0641
EC: 1.1.1.267
UniProt
Find proteins for Q8IKG4 (Plasmodium falciparum (isolate 3D7))
Explore Q8IKG4 
Go to UniProtKB:  Q8IKG4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8IKG4
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
RF7 Binding MOAD:  4Y6R IC50: 3300 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.189 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.399α = 89.64
b = 54.852β = 105.4
c = 85.208γ = 107.61
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
VetenskapradetSweden--

Revision History  (Full details and data files)

  • Version 1.0: 2015-04-01
    Type: Initial release
  • Version 1.1: 2015-04-22
    Changes: Database references
  • Version 1.2: 2024-01-10
    Changes: Data collection, Database references, Derived calculations, Refinement description