7KES

Crystal structure of meta-AAC0038, an environmental aminoglycoside resistance enzyme, mutant H168A in complex with apramycin and CoA

Summary for 7KES

• Entry DOI: 10.2210/pdb7kes/pdb
• Related: 5HT0 6mmz 6mn0 6mn1 6mn2
• Descriptor: Aminoglycoside N(3)-acetyltransferase, GLYCEROL, COENZYME A, ... (6 entities in total)
• Functional Keywords: antibiotic_nat family, acetyltransferase, aminoglycoside, antibiotic resistance, metagenome, soil, csgid, transferase, center for structural genomics of infectious diseases, national institute of allergy and infectious diseases, niaid, transferase-antibiotic complex, transferase/antibiotic
• Biological source: uncultured bacterium
• Total number of polymer chains: 2
• Total formula weight: 60326.75

Authors

Stogios, P.J.,Skarina, T.,Michalska, K.,Xu, Z.,Yim, V.,Savchenko, A.,Joachimiak, A.,Satchell, K.J.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2020-10-12, release date: 2020-10-21, Last modification date: 2023-10-18)

Primary citation

Stogios, P.J.,Bordeleau, E.,Xu, Z.,Skarina, T.,Evdokimova, E.,Chou, S.,Diorio-Toth, L.,D'Souza, A.W.,Patel, S.,Dantas, G.,Wright, G.D.,Savchenko, A.
Structural and molecular rationale for the diversification of resistance mediated by the Antibiotic_NAT family.
Commun Biol, 5:263-263, 2022

PubMed Abstract: The environmental microbiome harbors a vast repertoire of antibiotic resistance genes (ARGs) which can serve as evolutionary predecessors for ARGs found in pathogenic bacteria, or can be directly mobilized to pathogens in the presence of selection pressures. Thus, ARGs from benign environmental bacteria are an important resource for understanding clinically relevant resistance. Here, we conduct a comprehensive functional analysis of the Antibiotic_NAT family of aminoglycoside acetyltransferases. We determined a pan-family antibiogram of 21 Antibiotic_NAT enzymes, including 8 derived from clinical isolates and 13 from environmental metagenomic samples. We find that environment-derived representatives confer high-level, broad-spectrum resistance, including against the atypical aminoglycoside apramycin, and that a metagenome-derived gene likely is ancestral to an aac(3) gene found in clinical isolates. Through crystallographic analysis, we rationalize the molecular basis for diversification of substrate specificity across the family. This work provides critical data on the molecular mechanism underpinning resistance to established and emergent aminoglycoside antibiotics and broadens our understanding of ARGs in the environment.

PubMed: 35338238
DOI: 10.1038/s42003-022-03219-w

Experimental method

X-RAY DIFFRACTION (2.36 Å)