Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase

  • Chung, Scisung (Department of Life Sciences, Pohang University of Science and Technology) ;
  • Kim, Sulhee (Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Ryu, Sung Ho (Department of Life Sciences, Pohang University of Science and Technology) ;
  • Hwang, Kwang Yeon (Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University) ;
  • Cho, Yunje (Department of Life Sciences, Pohang University of Science and Technology)
  • Received : 2019.11.25
  • Accepted : 2019.12.14
  • Published : 2020.04.30
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Abstract

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 isoleucyl-tRNA 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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