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

Autor: Lotte Lambertsen, Georgy Smyshlyaev, Orsolya Barabas, Aleksandra Bebel, Eike C. Schulz, Peer Bork, Carlos Rojas-Cordova, Kristoffer Forslund, Anna Rubio-Cosials, Ezgi Karaca
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Models
Molecular
antibiotic resistance
tyrosine recombinase
vancomycin
Transposases
Crystallography
X-Ray
Homology (biology)
chemistry.chemical_compound
Catalytic Domain
Enterococcus faecalis
gene transfer
Transposase
Genetics
Tn916-like transposon family
Recombinant Proteins
Dna complex
conjugative transposition
Protein Binding
Transposable element
DNA
Bacterial
030106 microbiology
multidrug-resistant bacteria
Biology
Molecular Dynamics Simulation
Cleavage (embryo)
General Biochemistry
Genetics and Molecular Biology
Article
03 medical and health sciences
Antibiotic resistance
ddc:570
Drug Resistance
Bacterial
ddc:610
Amino Acid Sequence
DNA Cleavage
crystallography
DNA complex
Binding Sites
Base Sequence
Protein Structure
Tertiary
Multiple drug resistance
030104 developmental biology
chemistry
Cardiovascular and Metabolic Diseases
DNA Transposable Elements
Mutagenesis
Site-Directed
Nucleic Acid Conformation
Sequence Alignment
DNA
Tn1549 transposon
Zdroj: Cell
Cell 173(1), 208-220 (2018). doi:10.1016/j.cell.2018.02.032
DOI: 10.3204/pubdb-2019-00221
Popis: Summary 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.
Graphical Abstract
Highlights • Antibiotic resistance-carrying conjugative transposon integrase structure revealed • DNA distortion and special cleavage site allow insertion into diverse genomic sites • Key structural features are conserved among numerous conjugative transposons • Structures uncover auto-inhibition, allowing transposition antagonist design
Structures of a conjugative transposase caught in the act reveal valuable mechanistic insight and point to potential strategies for limiting dissemination of antibiotic resistance.
Databáze: OpenAIRE
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