8G7I

Crystal Structure of FosB from Bacillus cereus with Zinc and Sulfate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 

Starting Model: experimental
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Ligand Structure Quality Assessment 


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Literature

Identification and analysis of small molecule inhibitors of FosB from Staphylococcus aureus.

Travis, S.Green, K.D.Thamban Chandrika, N.Pang, A.H.Frantom, P.A.Tsodikov, O.V.Garneau-Tsodikova, S.Thompson, M.K.

(2023) RSC Med Chem 14: 947-956

  • DOI: https://doi.org/10.1039/d3md00113j
  • Primary Citation of Related Structures:  
    8E7Q, 8E7R, 8G7F, 8G7G, 8G7H, 8G7I

  • PubMed Abstract: 

    Antimicrobial resistance (AMR) poses a significant threat to human health around the world. Though bacterial pathogens can develop resistance through a variety of mechanisms, one of the most prevalent is the production of antibiotic-modifying enzymes like FosB, a Mn 2+ -dependent l-cysteine or bacillithiol (BSH) transferase that inactivates the antibiotic fosfomycin. FosB enzymes are found in pathogens such as Staphylococcus aureus , one of the leading pathogens in deaths associated with AMR. fosB gene knockout experiments establish FosB as an attractive drug target, showing that the minimum inhibitory concentration (MIC) of fosfomycin is greatly reduced upon removal of the enzyme. Herein, we have identified eight potential inhibitors of the FosB enzyme from S. aureus by applying high-throughput in silico screening of the ZINC15 database with structural similarity to phosphonoformate, a known FosB inhibitor. In addition, we have obtained crystal structures of FosB complexes to each compound. Furthermore, we have kinetically characterized the compounds with respect to inhibition of FosB. Finally, we have performed synergy assays to determine if any of the new compounds lower the MIC of fosfomycin in S. aureus . Our results will inform future studies on inhibitor design for the FosB enzymes.


  • Organizational Affiliation

    Department of Chemistry & Biochemistry, The University of Alabama Box 870336, 250 Hackberry Lane Tuscaloosa AL 35487 USA [email protected] +(205) 348 8439.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Metallothiol transferase FosB
A, B
138Bacillus cereusMutation(s): 0 
Gene Names: fosBBCE_2111
EC: 2.5.1
UniProt
Find proteins for Q739M9 (Bacillus cereus (strain ATCC 10987 / NRS 248))
Explore Q739M9 
Go to UniProtKB:  Q739M9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ739M9
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SO4 (Subject of Investigation/LOI)
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A],
N [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

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G [auth B]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
M [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
FMT
Query on FMT

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B],
I [auth B],
J [auth B],
K [auth B]
FORMIC ACID
C H2 O2
BDAGIHXWWSANSR-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
D [auth A],
L [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.83 Å
  • R-Value Free: 0.188 
  • R-Value Work: 0.159 
  • R-Value Observed: 0.161 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 63.494α = 90
b = 68.402β = 90
c = 70.063γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
SCALEPACKdata scaling
PHASERphasing
HKL-2000data reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States1R15GM148956

Revision History  (Full details and data files)

  • Version 1.0: 2023-06-14
    Type: Initial release
  • Version 1.1: 2024-05-22
    Changes: Data collection