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KMID : 0578320200430040350
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Molecules and Cells
2020 Volume.43 No. 4 p.350 ~ p.359
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Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase
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Chung Sci-Sung
Kim Sul-Hee
Ryu Sung-Ho
Hwang Kwang-Yeon
Cho Yun-Je
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Abstract
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Pathogenic aminoacyl-tRNA synthetases (ARSs) are attractive targets for anti-infective agents because their catalytic active sites are different from those of human ARSs. Mupirocin is a topical antibiotic that specifically inhibits bacterial isoleucy-ltRNA synthetase (IleRS), resulting in a block to protein synthesis. Previous studies on Thermus thermophilus IleRS indicated that mupirocin-resistance of eukaryotic IleRS is primarily due to differences in two amino acids, His581 and Leu583, in the active site. However, without a eukaryotic IleRS structure, the structural basis for mupirocin-resistance of eukaryotic IleRS remains elusive. Herein, we determined the crystal structure of Candida albicans IleRS complexed with Ile-AMP at 2.9 A resolution. The largest difference between eukaryotic and prokaryotic IleRS enzymes is closure of the active site pocket by Phe55 in the HIGH loop; Arg410 in the CP core loop; and the second Lys in the KMSKR loop. The Ile-AMP product is lodged in a closed active site, which may restrict its release and thereby enhance catalytic efficiency. The compact active site also prevents the optimal positioning of the 9-hydroxynonanoic acid of mupirocin and plays a critical role in resistance of eukaryotic IleRS to anti-infective agents.
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KEYWORD
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active site closure, aminoacyl-tRNA synthetases, anti-infective agents, crystal structure, mupirocin
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