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PDBsum entry 6ayh
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Transcription
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PDB id
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6ayh
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References listed in PDB file
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Key reference
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Title
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Structural basis for the regulation of β-Glucuronidase expression by human gut enterobacteriaceae.
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Authors
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M.S.Little,
S.J.Pellock,
W.G.Walton,
A.Tripathy,
M.R.Redinbo.
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Ref.
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Proc Natl Acad Sci U S A, 2018,
115,
E152.
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PubMed id
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Abstract
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The gut microbiota harbor diverse β-glucuronidase (GUS) enzymes that liberate
glucuronic acid (GlcA) sugars from small-molecule conjugates and complex
carbohydrates. However, only the Enterobacteriaceae family of human
gut-associated Proteobacteria maintain a GUS operon under the transcriptional
control of a glucuronide repressor, GusR. Despite its potential importance
inEscherichia,Salmonella,Klebsiella,Shigella,
andYersiniaopportunistic pathogens, the structure of GusR has not been
examined. Here, we explore the molecular basis for GusR-mediated regulation of
GUS expression in response to small-molecule glucuronides. Presented are
2.1-Å-resolution crystal structures of GusRs fromEscherichia
coliandSalmonella entericain complexes with a glucuronide ligand. The
GusR-specific DNA operator site in the regulatory region of theE. coliGUS
operon is identified, and structure-guided GusR mutants pinpoint the residues
essential for DNA binding and glucuronide recognition. Interestingly, the
endobiotic estradiol-17-glucuronide and the xenobiotic
indomethacin-acyl-glucuronide are found to exhibit markedly differential binding
to these GusR orthologs. Using structure-guided mutations, we are able to
transferE. coliGusR's preferential DNA and glucuronide binding affinity
toS. entericaGusR. Structures of putative GusR orthologs from
GUS-encoding Firmicutes species also reveal functionally unique features of the
Enterobacteriaceae GusRs. Finally, dominant-negative GusR variants are validated
in cell-based studies. These data provide a molecular framework toward
understanding the control of glucuronide utilization by opportunistic pathogens
in the human gut.
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