Structural and biochemical analyses of an aminoglycoside 2 '-N-acetyltransferase from Mycolicibacterium smegmatis
- 주제(기타) Multidisciplinary Sciences
- 설명문(일반) [Jeong, Chang-Sook; Hwang, Jisub; Do, Hackwon; Lee, Jun Hyuck] Korea Polar Res Inst, Res Unit Cryogen Novel Mat, Incheon 21990, South Korea; [Jeong, Chang-Sook; Hwang, Jisub; Lee, Jun Hyuck] Univ Sci & Technol, Dept Polar Sci, Incheon 21990, South Korea; [Cha, Sun-Shin] Ewha Womans Univ, Dept Chem & Nanosci, Seoul 03760, South Korea; [Oh, Tae-Jin] SunMoon Univ, Grad Sch, Dept Life Sci & Biochem Engn, Asan 31460, South Korea; [Oh, Tae-Jin] Genome Based BioIT Convergence Inst, Asan 31460, South Korea; [Oh, Tae-Jin] SunMoon Univ, Dept Pharmaceut Engn & Biotechnol, Asan 31460, South Korea; [Kim, Hak Jun] Pukyong Natl Univ, Dept Chem, 45 Yongso Ro, Busan 48513, South Korea; [Park, Hyun Ho] Chung Ang Univ, Coll Pharm, Seoul 06974, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published, gold
- 발행기관 NATURE RESEARCH
- 발행년도 2020
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000175476
- 본문언어 영어
- Published As http://dx.doi.org/10.1038/s41598-020-78699-z
- PubMed https://pubmed.ncbi.nlm.nih.gov/33299080
초록/요약
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 alpha 4-helix and beta 8-beta 9 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.
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