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X-ray structure of the AAC(6')-Ii antibiotic resistance enzyme at 1.8 Å resolution; examination of oligomeric arrangements in GNAT superfamily members

¹ Departments of Biochemistry and Microbiology and Immunology, McGill University, Montreal, Quebec H3A 2B4, Canada
² Antimicrobial Research Centre and Department of Biochemistry, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

Reprint requests to: Albert M. Berghuis, Departments of Biochemistry and Microbiology and Immunology, McGill University, 3775 University St., Room 613, Montreal, Quebec H3A 2B4, Canada; e-mail: albert.berghuis{at}mcgill.ca; fax: (514) 398-7052.

The rise of antibiotic resistance as a public health concern has led to increased interest in studying the ways in which bacteria avoid the effects of antibiotics. Enzymatic inactivation by several families of enzymes has been observed to be the predominant mechanism of resistance to aminoglycoside antibiotics such as kanamycin and gentamicin. Despite the importance of acetyltransferases in bacterial resistance to aminoglycoside antibiotics, relatively little is known about their structure and mechanism. Here we report the three-dimensional atomic structure of the aminoglycoside acetyltransferase AAC(6')-Ii in complex with coenzyme A (CoA). This structure unambiguously identifies the physiologically relevant AAC(6')-Ii dimer species, and reveals that the enzyme structure is similar in the AcCoA and CoA bound forms. AAC(6')-Ii is a member of the GCN5-related N-acetyltransferase (GNAT) superfamily of acetyltransferases, a diverse group of enzymes that possess a conserved structural motif, despite low sequence homology. AAC(6')-Ii is also a member of a subset of enzymes in the GNAT superfamily that form multimeric complexes. The dimer arrangements within the multimeric GNAT superfamily members are compared, revealing that AAC(6')-Ii forms a dimer assembly that is different from that observed in the other multimeric GNAT superfamily members. This different assembly may provide insight into the evolutionary processes governing dimer formation.

Keywords: Aminoglycoside acetyltransferase; antibiotic resistance; X-ray crystallography; N-acetyltransferase; dimerization

Abbreviations: AAC, aminoglycoside acetyltransferase • AAC(2')-Ic, aminoglycoside 2'-acetyltransferase type Ic • AAC(3)-Ia, aminoglycoside 3-acetyltransferase type Ia • AAC(6')-Ii, aminoglycoside 6'-acetyltransferase type Ii • AANAT, serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase) • AcCoA, acetyl coenzyme A • CoA, coenzyme A • GNAT, GCN5-related N-acetyltransferase • hPCAF, human histone acetyltransferase domain of P300/CBP associating factor • yGCN5, yeast GCN5 transcriptional activator • tGCN5, Tetramymena thermophila • GCN5, histone acetyltransferase domain • yHPA2, yeast histone acetyltransferase HPA2 • yHAT1, yeast histone acetyltransferase HAT1 • cNMT, Candida albicans N-myristoyl transferase • yNMT, yeast N-myristoyl transferase • GNA1, Saccharomyces cerevisiae GCN5-related N-acetyltransferase • RMSD, root-mean-square deviation

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