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Cell. 2018 Mar 22;173(1):208-220.e20. doi: 10.1016/j.cell.2018.02.032. Epub 2018 Mar 15.

Transposase-DNA Complex Structures Reveal Mechanisms for Conjugative Transposition of Antibiotic Resistance.

Author information

1
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
2
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany; Hamburg Outstation, European Molecular Biology Laboratory, 22603 Hamburg, Germany.
3
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany; European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton CB10 1SD, UK.
4
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany; Izmir Biomedicine and Genome Center (IBG), 35340 Izmir, Turkey.
5
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany; Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; Molecular Medicine Partnership Unit, 69120 Heidelberg, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, 97074 Würzburg, Germany.
6
Structural and Computational Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany. Electronic address: barabas@embl.de.

Abstract

Conjugative transposition drives the emergence of multidrug resistance in diverse bacterial pathogens, yet the mechanisms are poorly characterized. The Tn1549 conjugative transposon propagates resistance to the antibiotic vancomycin used for severe drug-resistant infections. Here, we present four high-resolution structures of the conserved Y-transposase of Tn1549 complexed with circular transposon DNA intermediates. The structures reveal individual transposition steps and explain how specific DNA distortion and cleavage mechanisms enable DNA strand exchange with an absolute minimum homology requirement. This appears to uniquely allow Tn916-like conjugative transposons to bypass DNA homology and insert into diverse genomic sites, expanding gene transfer. We further uncover a structural regulatory mechanism that prevents premature cleavage of the transposon DNA before a suitable target DNA is found and generate a peptide antagonist that interferes with the transposase-DNA structure to block transposition. Our results reveal mechanistic principles of conjugative transposition that could help control the spread of antibiotic resistance genes.

KEYWORDS:

DNA complex; Tn1549 transposon; Tn916-like transposon family; antibiotic resistance; conjugative transposition; crystallography; gene transfer; multidrug-resistant bacteria; tyrosine recombinase; vancomycin

PMID:
29551265
PMCID:
PMC5871717
DOI:
10.1016/j.cell.2018.02.032
[Indexed for MEDLINE]
Free PMC Article

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