9MH5

Structure of N-3 aminoglycoside acetyltransferase XI (AAC(3)-XI) in complex with coenzyme A and acetylated sisomicin

Summary for 9MH5

• Entry DOI: 10.2210/pdb9mh5/pdb
• Descriptor: Aminoglycoside N-acetyltransferase AAC(3)-XI, COENZYME A, acetylsisomicin, ... (5 entities in total)
• Functional Keywords: antibiotic resistance, aminoglycosides, transferase
• Biological source: Corynebacterium striatum
• Total number of polymer chains: 2
• Total formula weight: 35494.25

Authors

Zielinski, M.,Hemmings, M.,Golkar, T.,Blanchet, J.,Berghuis, A.M. (deposition date: 2024-12-11, release date: 2025-09-03, Last modification date: 2025-09-17)

Primary citation

Hemmings, M.,Zielinski, M.,Golkar, T.,Blanchet, J.,Pistofidis, A.,Munro, K.,Schmeing, T.M.,Bohle, D.S.,Berghuis, A.M.
Enzyme-mediated aminoglycoside resistance without target mimicry.
Commun Chem, 8:258-258, 2025

PubMed Abstract: The primary mode of resistance to aminoglycoside antibiotics is through chemical modification catalyzed by aminoglycoside-modifying enzymes. Numerous structural studies of these enzymes have invariably shown that they bind aminoglycosides in the same lowest-energy conformation as the intended target for these antibiotics, the A site of the bacterial ribosome. Presumably, the binding mode mimicry enables these enzymes to compete successfully with the target, thus conferring effective resistance. Here we present the first structural and functional studies of two aminoglycoside-modifying enzymes that do not use target mimicry, AAC(3)-Ia and AAC(3)-XIa. X-ray diffraction studies reveal that these enzymes bind aminoglycoside antibiotics in a conformation where the central 2-deoxystreptamine ring is in boat conformation. The effect of this non-canonical binding mode on the enzymes' ability to modify antibiotics is assessed in silico and in vitro, and its impact for conferring resistance is assessed in vivo. Overall, the results show that target mimicry, while advantageous, is not an essential strategy for aminoglycoside-modifying enzymes to be effective in conferring resistance.

PubMed: 40855189
DOI: 10.1038/s42004-025-01666-0

Experimental method

X-RAY DIFFRACTION (1.46 Å)