6AZH

Clostridium perfringens putative fatty acid metabolism regulator

Summary for 6AZH

• Entry DOI: 10.2210/pdb6azh/pdb
• Descriptor: TetR family transcriptional regulator (2 entities in total)
• Functional Keywords: regulator, transcription
• Biological source: Clostridium perfringens
• Total number of polymer chains: 2
• Total formula weight: 44868.34

Authors

William, W.G.,Redinbo, M.R. (deposition date: 2017-09-11, release date: 2017-12-20, Last modification date: 2024-10-30)

Primary citation

Little, M.S.,Pellock, S.J.,Walton, W.G.,Tripathy, A.,Redinbo, M.R.
Structural basis for the regulation of beta-glucuronidase expression by human gut Enterobacteriaceae.
Proc. Natl. Acad. Sci. U.S.A., 115:E152-E161, 2018

PubMed Abstract: 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 in , , , , and opportunistic 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 from and in complexes with a glucuronide ligand. The GusR-specific DNA operator site in the regulatory region of the GUS 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 transfer GusR's preferential DNA and glucuronide binding affinity to GusR. 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.

PubMed: 29269393
DOI: 10.1073/pnas.1716241115

Experimental method

X-RAY DIFFRACTION (1.75 Å)