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

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.

SUBMITTER: Zielinski M

PROVIDER: S-EPMC9348671 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Zieliński Michał M Blanchet Jonathan J Hailemariam Sophia S Berghuis Albert M AM

PloS one 20220803 8

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 coen ...[more]

PMID: 35921328

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