6VOU

Aminoglycoside N-2'-Acetyltransferase-Ia [AAC(2')-Ia] in complex with acetylated-plazomicin and CoA

Summary for 6VOU

• Entry DOI: 10.2210/pdb6vou/pdb
• Related: 6VR2 6VR3 6VTA
• Descriptor: Aminoglycoside 2'-N-acetyltransferase, COENZYME A, 3,3',3''-phosphanetriyltripropanoic acid, ... (6 entities in total)
• Functional Keywords: acetyltransferase, gnat superfamily, transferase
• Biological source: Providencia stuartii
• Total number of polymer chains: 2
• Total formula weight: 43902.90

Authors

Bassenden, A.V.,Berghuis, A.M. (deposition date: 2020-01-31, release date: 2021-06-02, Last modification date: 2024-03-06)

Primary citation

Golkar, T.,Bassenden, A.V.,Maiti, K.,Arya, D.P.,Schmeing, T.M.,Berghuis, A.M.
Structural basis for plazomicin antibiotic action and resistance.
Commun Biol, 4:729-729, 2021

PubMed Abstract: The approval of plazomicin broadened the clinical library of aminoglycosides available for use against emerging bacterial pathogens. Contrarily to other aminoglycosides, resistance to plazomicin is limited; still, instances of resistance have been reported in clinical settings. Here, we present structural insights into the mechanism of plazomicin action and the mechanisms of clinical resistance. The structural data reveal that plazomicin exclusively binds to the 16S ribosomal A site, where it likely interferes with the fidelity of mRNA translation. The unique extensions to the core aminoglycoside scaffold incorporated into the structure of plazomicin do not interfere with ribosome binding, which is analogously seen in the binding of this antibiotic to the AAC(2')-Ia resistance enzyme. The data provides a structural rationale for resistance conferred by drug acetylation and ribosome methylation, i.e., the two mechanisms of resistance observed clinically. Finally, the crystal structures of plazomicin in complex with both its target and the clinically relevant resistance factor provide a roadmap for next-generation drug development that aims to ameliorate the impact of antibiotic resistance.

PubMed: 34117352
DOI: 10.1038/s42003-021-02261-4

Experimental method

X-RAY DIFFRACTION (1.95 Å)