Database accession: MF7000323
Name: FosB (Bacillus cereus)
PDB ID: 8g7f
Experimental method: X-ray (2.04 Å)
Assembly: Homodimer
Source organism: Bacillus cereus
Primary publication of the structure:
Travis S, Green KD, Thamban Chandrika N, Pang AH, Frantom PA, Tsodikov OV, Garneau-Tsodikova S, Thompson MK
Identification and analysis of small molecule inhibitors of FosB from .
(2023) Rsc Med Chem 14: 947-956
PMID: 37252104
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 Mn2+-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.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
magnesium ion binding magnesium ion binding
transferase activity, transferring alkyl or aryl (other than methyl) groups transferase activity, transferring alkyl or aryl (other than methyl) groups
Biological process:
response to antibiotic response to antibiotic
Cellular component:
cytoplasm cytoplasm
Structural annotations of the participating protein chains.Entry contents: 2 distinct polypeptide molecules
Chains: A, B
Notes: All chains according to the most probable oligomerization state stored in PDBe were considered.
Number of unique protein segments: 1
Name: Metallothiol transferase FosB
Source organism: Bacillus cereus
Length: 138 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMLNGINHLCFSVSNLEDSIEFYEKVLEGELLVRGRKLAYFNICGVWVALNEEIHIPRNEIYQSYTHIAFSVEQKDFESLLQRLEENDVHILKGRERDVRDCESIYFVDPDGHKFEFHSGTLQDRLNYYREDKPHMTFY
UniProtKB AC: Q739M9 (positions: 1-138)
Coverage: 100%
Name: Metallothiol transferase FosB
Source organism: Bacillus cereus
Length: 138 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMLNGINHLCFSVSNLEDSIEFYEKVLEGELLVRGRKLAYFNICGVWVALNEEIHIPRNEIYQSYTHIAFSVEQKDFESLLQRLEENDVHILKGRERDVRDCESIYFVDPDGHKFEFHSGTLQDRLNYYREDKPHMTFY
UniProtKB AC: Q739M9 (positions: 1-138)
Coverage: 100%
Evidence demonstrating that the participating proteins are unstructured prior to the interaction and their folding is coupled to binding. Representative domain in related structures: Glyoxalase/Bleomycin resistance protein/Dioxygenase superfamily
Evidence level: Indirect evidence
Evidence coverage: The full structure participates in mutual synergistic folding.
Complex Evidence:
The VOC superfamily of metalloenzymes is characterized by a three-dimensional domain-swapped arrangement of tandem βαβββ-motifs (PMID:24447055). The original gene duplication event led to the βαβββ tandem structure, which appears to require dimerization for stability. Two different forms of domain-swapped dimers may coexist in solution (PMID:12121648) in which both subunits of the homodimer participate in coordination of each metal ion and formation of the U-shaped active sites in the enzyme (PMID:24004181). The complex is predominantly dimeric in solution (gel filtration) (PMID:12121648).
Chain A:
N/A
Chain B:
N/A
Surface and contacts features:
Structures from the PDB that contain the same number of proteins, and the proteins from the two structures show a sufficient degree of pairwise similarity, i.e. they belong to the same UniRef90 cluster (the full proteins exhibit at least 90% sequence identity) and convey roughly the same region to their respective interactions (the two regions from the two proteins share a minimum of 70% overlap). Download the CIF file (.cif)
Download this entry's XML file (.xml)
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