Structural elucidation of substrate-bound aminoglycoside acetyltransferase (3)-IIIa

PLoS One. 2022 Aug 3;17(8):e0269684. doi: 10.1371/journal.pone.0269684. eCollection 2022.

Abstract

Canonical aminoglycosides are a large group of antibiotics, where the part of chemical diversity stems from the substitution of the neamine ring system on positions 5 and 6. Certain aminoglycoside modifying enzymes can modify a broad range of 4,5- and 4,6-disubstituted aminoglycosides, with some as many as 15. This study presents the structural and kinetic results describing a promiscuous aminoglycoside acetyltransferase AAC(3)-IIIa. This enzyme has been crystallized in ternary complex with coenzyme A and 4,5- and 4,6-disubstituted aminoglycosides. We have followed up this work with kinetic characterization utilizing a panel of diverse aminoglycosides, including a next-generation aminoglycoside, plazomicin. Lastly, we observed an alternative binding mode of gentamicin in the aminoglycoside binding site, which was proven to be a crystallographic artifact based on mutagenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases* / metabolism
  • Aminoglycosides* / chemistry
  • Anti-Bacterial Agents / chemistry
  • Substrate Specificity

Substances

  • Aminoglycosides
  • Anti-Bacterial Agents
  • Acetyltransferases
  • aminoglycoside acetyltransferase