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| Subject Categories: Structural Biology | Microbiology & Pathogens |
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| The EMBO Journal
(2002) 21, 2323–2331, doi: 10.1093/emboj/21.10.2323 |
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| Substrate promiscuity of an aminoglycoside antibiotic resistance enzyme via target mimicry |
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| Desiree H. Fong1 and Albert M. Berghuis1, 2 |
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1 Department of Biochemistry McGill University, 3775 University Street, Montreal, Quebec H3A 2B4, Canada 2 Department of Microbiology and Immunology, McGill University, 3775 University Street, Montreal, Quebec H3A 2B4, Canada To whom correspondence should be addressed Albert M. Berghuis, albert.berghuis@mcgill.ca Received 13 February 2002; Revised 25 March 2002; Accepted 25 March 2002. |
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| Abstract |
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| The misuse of antibiotics has selected for bacteria that have evolved mechanisms for evading the effects of these drugs. For aminoglycosides, a group of clinically important bactericidal antibiotics that target the A-site of the 16S ribosomal RNA, the most common mode of resistance is enzyme-catalyzed chemical modification of the drug. While aminoglycosides are structurally diverse, a single enzyme can confer resistance to many of these antibiotics. For example, the aminoglycoside kinase APH(3')-IIIa, produced by pathogenic Gram-positive bacteria such as enterococci and staphylococci, is capable of detoxifying at least 10 distinct aminoglycosides. Here we describe the crystal structures of APH(3')-IIIa in complex with ADP and kanamycin A or neomycin B. These structures reveal that the basis for this enzyme's substrate promiscuity is the presence of two alternative subsites in the antibiotic binding pocket. Furthermore, comparison between the A-site of the bacterial ribosome and APH(3')-IIIa shows that mimicry is the second major factor in dictating the substrate spectrum of APH(3')-IIIa. These results suggest a potential strategy for drug design aimed at circumventing antibiotic resistance. |
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| Keywords: antibiotic resistance, crystal structure, functional mimicry, kinase, multidrug binding |
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