5ZLF

CRYSTAL STRUCTURE OF OCTAPRENYL PYROPHOSPHATE SYNTHASE FROM ESCHERICHIA COLI WITH ligand BPH-629


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.299 
  • R-Value Work: 0.241 
  • R-Value Observed: 0.243 

Starting Model: experimental
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This is version 1.2 of the entry. See complete history


Literature

Discovery of Lipophilic Bisphosphonates That Target Bacterial Cell Wall and Quinone Biosynthesis.

Malwal, S.R.Chen, L.Hicks, H.Qu, F.Liu, W.Shillo, A.Law, W.X.Zhang, J.Chandnani, N.Han, X.Zheng, Y.Chen, C.C.Guo, R.T.AbdelKhalek, A.Seleem, M.N.Oldfield, E.

(2019) J Med Chem 62: 2564-2581

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b01878
  • Primary Citation of Related Structures:  
    5ZE6, 5ZHE, 5ZLF

  • PubMed Abstract: 

    We report that alkyl-substituted bisphosphonates have activity against Bacillus anthracis Sterne (0.40 μg/mL), Mycobacterium smegmatis (1.4 μg/mL), Bacillus subtilis (1.0 μg/mL), and Staphylococcus aureus (13 μg/mL). In many cases, there is no effect of serum binding, as well as low activity against a human embryonic kidney cell line. Targeting of isoprenoid biosynthesis is involved with 74 having IC 50 values of ∼100 nM against heptaprenyl diphosphate synthase and 200 nM against farnesyl diphosphate synthase. B. subtilis growth inhibition was rescued by addition of farnesyl diphosphate, menaquinone-4 (MK-4), or undecaprenyl phosphate (UP), and the combination of MK-4 and UP resulted in a 25× increase in ED 50 , indicating targeting of both quinone and cell wall biosynthesis. Clostridioides difficile was inhibited by 74, and since this organism does not synthesize quinones, cell wall biosynthesis is the likely target. We also solved three X-ray structures of inhibitors bound to octaprenyl diphosphate and/or undecaprenyl diphosphate synthases.


  • Organizational Affiliation

    Industrial Enzymes National Engineering Laboratory , Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , Tianjin 200208 , China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Octaprenyl diphosphate synthase
A, B, C, D
323Escherichia coli K-12Mutation(s): 0 
Gene Names: ispBcelyhbDb3187JW3154
EC: 2.5.1.90
UniProt
Find proteins for P0AD57 (Escherichia coli (strain K12))
Explore P0AD57 
Go to UniProtKB:  P0AD57
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP0AD57
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.85 Å
  • R-Value Free: 0.299 
  • R-Value Work: 0.241 
  • R-Value Observed: 0.243 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 149.344α = 90
b = 46.645β = 101.08
c = 215.741γ = 90
Software Package:
Software NamePurpose
HKL-2000data scaling
PHENIXrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-27
    Type: Initial release
  • Version 1.1: 2019-09-25
    Changes: Data collection, Database references
  • Version 1.2: 2023-11-22
    Changes: Data collection, Database references, Refinement description