7ZHD

Crystal structure of CtaZ in complex with Closthioamide

Summary for 7ZHD

• Entry DOI: 10.2210/pdb7zhd/pdb
• Related: 6WL5
• Descriptor: Transcription activator effector binding, ~{N}-[3-[[3-[3-[3-[3-[(4-hydroxyphenyl)carbothioylamino]propanethioylamino]propanethioylamino]propylamino]-3-sulfanylidene-propyl]amino]-3-sulfanylidene-propyl]-4-oxidanyl-benzenecarbothioamide, ZINC ION, ... (6 entities in total)
• Functional Keywords: gyrase-like domain, receptor, siderophore, self protection, antibiotic resistance, drug binding, lipid binding protein
• Biological source: Ruminiclostridium cellulolyticum
• Total number of polymer chains: 1
• Total formula weight: 18418.26

Authors

Gude, F.,Molloy, E.M.,Horch, T.,Dell, M.,Dunbar, K.L.,Krabbe, J.,Groll, M.,Hertweck, C. (deposition date: 2022-04-06, release date: 2022-11-09, Last modification date: 2024-06-19)

Primary citation

Gude, F.,Molloy, E.M.,Horch, T.,Dell, M.,Dunbar, K.L.,Krabbe, J.,Groll, M.,Hertweck, C.
A Specialized Polythioamide-Binding Protein Confers Antibiotic Self-Resistance in Anaerobic Bacteria.
Angew.Chem.Int.Ed.Engl., 61:e202206168-e202206168, 2022

PubMed Abstract: Understanding antibiotic resistance mechanisms is central to the development of anti-infective therapies and genomics-based drug discovery. Yet, many knowledge gaps remain regarding the resistance strategies employed against novel types of antibiotics from less-explored producers such as anaerobic bacteria, among them the Clostridia. Through the use of genome editing and functional assays, we found that CtaZ confers self-resistance against the copper chelator and gyrase inhibitor closthioamide (CTA) in Ruminiclostridium cellulolyticum. Bioinformatics, biochemical analyses, and X-ray crystallography revealed CtaZ as a founding member of a new group of GyrI-like proteins. CtaZ is unique in binding a polythioamide scaffold in a ligand-optimized hydrophobic pocket, thereby confining CTA. By genome mining using CtaZ as a handle, we discovered previously overlooked homologs encoded by diverse members of the phylum Firmicutes, including many pathogens. In addition to characterizing both a new role for a GyrI-like domain in self-resistance and unprecedented thioamide binding, this work aids in uncovering related drug-resistance mechanisms.

PubMed: 35852818
DOI: 10.1002/anie.202206168

Experimental method

X-RAY DIFFRACTION (1.65 Å)