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Structural and biochemical analyses of an aminoglycoside 2′-N-acetyltransferase from Mycolicibacterium smegmatis

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Title
Structural and biochemical analyses of an aminoglycoside 2′-N-acetyltransferase from Mycolicibacterium smegmatis
Other Titles
항생물질 변형 및 항생제 내성에 관여하는 aminoglycoside 2'-N-acetyltransferase 효소의 삼차구조와 생화학적 특성 연구
Authors
Jeong, Chang Sook
Hwang, Jisub
Do, Hackwon
Cha, Sun-Shin
Oh, Tae-Jin
Kim, Hak Jun
Park, Hyun Ho
Lee, Jun Hyuck
Subject
Science & Technology
Keywords
X-ray crystallography; aminoglycoside acetyltransferase; antibiotics; crystal structure
Issue Date
2020-12
Citation
Jeong, Chang Sook, et al. 2020. "Structural and biochemical analyses of an aminoglycoside 2′-N-acetyltransferase from Mycolicibacterium smegmatis". SCIENTIFIC REPORTS, 10(1): 1-14.
Abstract
The expression of aminoglycoside-modifying enzymes represents a survival strategy of antibiotic-resistant bacteria. Aminoglycoside 2'-N-acetyltransferase (AAC(2')) neutralizes aminoglycoside drugs by acetylation of their 2' amino groups in an acetyl coenzyme A (CoA)-dependent manner. To understand the structural features and molecular mechanism underlying AAC(2') activity, we overexpressed, purified, and crystallized AAC(2') from Mycolicibacterium smegmatis (AAC(2')-Id) and determined the crystal structures of its apo-form and ternary complexes with CoA and four different aminoglycosides (gentamicin, sisomicin, neomycin, and paromomycin). These AAC(2')-Id structures unraveled the binding modes of different aminoglycosides, explaining the broad substrate specificity of the enzyme. Comparative structural analysis showed that the α4-helix and β8?β9 loop region undergo major conformational changes upon CoA and substrate binding. Additionally, structural comparison between the present paromomycin-bound AAC(2')-Id structure and the previously reported paromomycin-bound AAC(6')-Ib and 30S ribosome structures revealed the structural features of paromomycin that are responsible for its antibiotic activity and AAC binding. Taken together, these results provide useful information for designing AAC(2') inhibitors and for the chemical modification of aminoglycosides.
URI
https://repository.kopri.re.kr/handle/201206/11810
DOI
http://dx.doi.org/10.1038/s41598-020-78699-z
Appears in Collections  
2020-2020, Development of potential candidates as antibiotics based on polar genetic resources (20-20) / Lee, Jun Hyuck (PM20030)
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