6VTA

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

Summary for 6VTA

• Entry DOI: 10.2210/pdb6vta/pdb
• Related: 6VOU 6VR2 6VR3
• Descriptor: Aminoglycoside 2'-N-acetyltransferase, ACETYL COENZYME *A, (2S)-N-[(1R,2S,3S,4R,5S)-4-[(2R,3R,4S,5S,6R)-6-(aminomethyl)-3,4,5-tris(oxidanyl)oxan-2-yl]oxy-5-azanyl-2-[(2S,3R,4S,5S ,6R)-4-azanyl-6-(hydroxymethyl)-3,5-bis(oxidanyl)oxan-2-yl]oxy-3-oxidanyl-cyclohexyl]-4-azanyl-2-oxidanyl-butanamide, ... (4 entities in total)
• Functional Keywords: acetyltransferase, gnat superfamily, transferase
• Biological source: Providencia stuartii
• Total number of polymer chains: 2
• Total formula weight: 43572.29

Authors

Bassenden, A.V.,Berghuis, A.M. (deposition date: 2020-02-12, release date: 2021-06-02, Last modification date: 2023-10-11)

Primary citation

Bassenden, A.V.,Dumalo, L.,Park, J.,Blanchet, J.,Maiti, K.,Arya, D.P.,Berghuis, A.M.
Structural and phylogenetic analyses of resistance to next-generation aminoglycosides conferred by AAC(2') enzymes.
Sci Rep, 11:11614-11614, 2021

PubMed Abstract: Plazomicin is currently the only next-generation aminoglycoside approved for clinical use that has the potential of evading the effects of widespread enzymatic resistance factors. However, plazomicin is still susceptible to the action of the resistance enzyme AAC(2')-Ia from Providencia stuartii. As the clinical use of plazomicin begins to increase, the spread of resistance factors will undoubtedly accelerate, rendering this aminoglycoside increasingly obsolete. Understanding resistance to plazomicin is an important step to ensure this aminoglycoside remains a viable treatment option for the foreseeable future. Here, we present three crystal structures of AAC(2')-Ia from P. stuartii, two in complex with acetylated aminoglycosides tobramycin and netilmicin, and one in complex with a non-substrate aminoglycoside, amikacin. Together, with our previously reported AAC(2')-Ia-acetylated plazomicin complex, these structures outline AAC(2')-Ia's specificity for a wide range of aminoglycosides. Additionally, our survey of AAC(2')-I homologues highlights the conservation of residues predicted to be involved in aminoglycoside binding, and identifies the presence of plasmid-encoded enzymes in environmental strains that confer resistance to the latest next-generation aminoglycoside. These results forecast the likely spread of plazomicin resistance and highlight the urgency for advancements in next-generation aminoglycoside design.

PubMed: 34078922
DOI: 10.1038/s41598-021-89446-3

Experimental method

X-RAY DIFFRACTION (1.42 Å)