3ANL

Crystal structure of 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) complexed with pyridin-2-ylmethylphosphonic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.186 

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This is version 1.3 of the entry. See complete history


Literature

Structures of 1-Deoxy-D-Xylulose-5-Phosphate Reductoisomerase/Lipophilic Phosphonate Complexes

Deng, L.Endo, K.Kato, M.Cheng, G.Yajima, S.Song, Y.

(2011) ACS Med Chem Lett 2: 165-170

  • DOI: https://doi.org/10.1021/ml100243r
  • Primary Citation of Related Structures:  
    3ANL, 3ANM, 3ANN

  • PubMed Abstract: 

    Fosmidomycin, a potent inhibitor of 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR), has antibacterial and antimalaria activity. Due to its poor pharmacokinetics, more lipophilic DXR inhibitors are needed. However, the hydrophobic binding site(s) in DXR remains elusive. Here, pyridine/quinoline containing phosphonates are identified to be DXR inhibitors with IC(50) values as low as 840 nM. We also report three DXR:inhibitor structures, revealing a novel binding mode. The indole group of Trp211 is found to move ~4.6 Å to open up a mainly hydrophobic pocket, where the pyridine/quinoline rings of the inhibitors are located and have strong π-π stacking/charge-transfer interactions with the indole. Docking studies demonstrate our structures could be used to predict the binding modes of other lipophilic DXR inhibitors. Overall, this work shows an important role of Trp211 in inhibitor recognition and provides a structural basis for future drug design and development.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
1-deoxy-D-xylulose 5-phosphate reductoisomerase
A, B
420Escherichia coli K-12Mutation(s): 0 
Gene Names: dxrispCyaeMb0173JW0168
EC: 1.1.1.267
UniProt
Find proteins for P45568 (Escherichia coli (strain K12))
Explore P45568 
Go to UniProtKB:  P45568
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP45568
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SYC Binding MOAD:  3ANL IC50: 4600 (nM) from 1 assay(s)
BindingDB:  3ANL IC50: 4600 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.184 
  • R-Value Observed: 0.186 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 181.717α = 90
b = 59.298β = 90
c = 87.166γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-02-23
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2011-10-19
    Changes: Database references
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description