4EVY

Crystal structure of aminoglycoside antibiotic 6'-N-acetyltransferase AAC(6')-Ig from Acinetobacter haemolyticus in complex with tobramycin

Summary for 4EVY

• Entry DOI: 10.2210/pdb4evy/pdb
• Descriptor: Aminoglycoside N(6')-acetyltransferase type 1, TOBRAMYCIN, POTASSIUM ION, ... (5 entities in total)
• Functional Keywords: center for structural genomics of infectious diseases (csgid), niaid, national institute of allergy and infectious diseases, gnat superfamily, gcn5-related n-acetyltransferase superfamily, n-acetyltransferase fold, antibiotic resistance, acetyl coenzyme a, intracellular, transferase-antibiotic complex, transferase/antibiotic
• Biological source: Acinetobacter haemolyticus
• Total number of polymer chains: 2
• Total formula weight: 38918.17

Authors

Stogios, P.J.,Evdokimova, E.,Minasov, G.,Yim, V.,Courvalin, P.,Savchenko, A.,Anderson, W.F.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2012-04-26, release date: 2012-05-09, Last modification date: 2023-09-13)

Primary citation

Stogios, P.J.,Kuhn, M.L.,Evdokimova, E.,Law, M.,Courvalin, P.,Savchenko, A.
Structural and Biochemical Characterization of Acinetobacter spp. Aminoglycoside Acetyltransferases Highlights Functional and Evolutionary Variation among Antibiotic Resistance Enzymes.
ACS Infect Dis., 3:132-143, 2017

PubMed Abstract: Modification of aminoglycosides by N-acetyltransferases (AACs) is one of the major mechanisms of resistance to these antibiotics in human bacterial pathogens. More than 50 enzymes belonging to the AAC(6') subfamily have been identified in Gram-negative and Gram-positive clinical isolates. Our understanding of the molecular function and evolutionary origin of these resistance enzymes remains incomplete. Here we report the structural and enzymatic characterization of AAC(6')-Ig and AAC(6')-Ih from Acinetobacter spp. The crystal structure of AAC(6')-Ig in complex with tobramycin revealed a large substrate-binding cleft remaining partially unoccupied by the substrate, which is in stark contrast with the previously characterized AAC(6')-Ib enzyme. Enzymatic analysis indicated that AAC(6')-Ig and -Ih possess a broad specificity against aminoglycosides but with significantly lower turnover rates as compared to other AAC(6') enzymes. Structure- and function-informed phylogenetic analysis of AAC(6') enzymes led to identification of at least three distinct subfamilies varying in oligomeric state, active site composition, and drug recognition mode. Our data support the concept of AAC(6') functionality originating through convergent evolution from diverse Gcn5-related-N-acetyltransferase (GNAT) ancestral enzymes, with AAC(6')-Ig and -Ih representing enzymes that may still retain ancestral nonresistance functions in the cell as provided by their particular active site properties.

PubMed: 27785912
DOI: 10.1021/acsinfecdis.6b00058

Experimental method

X-RAY DIFFRACTION (1.768 Å)