Database accession: MF7000492
Name: FosA3 with inhibitor (ANY1)
PDB ID: 5wep
Experimental method: X-ray (3.50 Å)
Assembly: Homodimer
Source organism: Escherichia coli
Primary publication of the structure:
Tomich AD, Klontz EH, Deredge D, Barnard JP, McElheny CL, Eshbach ML, Weisz OA, Wintrode P, Doi Y, Sundberg EJ, Sluis-Cremer N
Small-Molecule Inhibitor of FosA Expands Fosfomycin Activity to Multidrug-Resistant Gram-Negative Pathogens.
(2019) Antimicrob. Agents Chemother. 63:
PMID: 30642934
Abstract:
The spread of multidrug or extensively drug-resistant Gram-negative bacteria is a serious public health issue. There are too few new antibiotics in development to combat the threat of multidrug-resistant infections, and consequently the rate of increasing antibiotic resistance is outpacing the drug development process. This fundamentally threatens our ability to treat common infectious diseases. Fosfomycin (FOM) has an established track record of safety in humans and is highly active against Escherichia coli, including multidrug-resistant strains. However, many other Gram-negative pathogens, including the "priority pathogens" Klebsiella pneumoniae and Pseudomonas aeruginosa, are inherently resistant to FOM due to the chromosomal fosA gene, which directs expression of a metal-dependent glutathione S-transferase (FosA) that metabolizes FOM. In this study, we describe the discovery and biochemical and structural characterization of ANY1 (3-bromo-6-[3-(3-bromo-2-oxo-1H-pyrazolo[1,5-a]pyrimidin-6-yl)-4-nitro-1H-pyrazol-5-yl]-1H-pyrazolo[1,5-a]pyrimidin-2-one), a small-molecule active-site inhibitor of FosA. Importantly, ANY1 potentiates FOM activity in representative Gram-negative pathogens. Collectively, our study outlines a new strategy to expand FOM activity to a broader spectrum of Gram-negative pathogens, including multidrug-resistant strains.
Annotations from the GeneOntology database. Only terms that fit at least two of the interacting proteins are shown. Molecular function:
metal ion binding metal ion binding
transferase activity transferase activity
Biological process: not assigned
Cellular component: not assigned
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: FosA3
Source organism: Escherichia coli
Length: 138 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMLQGLNHLTLAVSDLASSLAFYQQLPGMRLHASWDSGAYLSCGALWLCLSLDEQRRKTPPQESDYTHYAFSVAEEEFAGVVALLAQAGAEVWKDNRSEGASYYFLDPDGHKLELHVGNLAQRLAACRERPYKGMVFFD
UniProtKB AC: D7UQM0 (positions: 1-138)
Coverage: 100%
Name: FosA3
Source organism: Escherichia coli
Length: 138 residues
Sequence:Sequence according to the corresponding UniProt protein segmentMLQGLNHLTLAVSDLASSLAFYQQLPGMRLHASWDSGAYLSCGALWLCLSLDEQRRKTPPQESDYTHYAFSVAEEEFAGVVALLAQAGAEVWKDNRSEGASYYFLDPDGHKLELHVGNLAQRLAACRERPYKGMVFFD
UniProtKB AC: D7UQM0 (positions: 1-137)
Coverage: 99%
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)
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