Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase
Scisung Chung1, Sulhee Kim2, Sung Ho Ryu1, Kwang Yeon Hwang2, and Yunje Cho1,*
1Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, Korea, 2Division of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Korea
Received November 25, 2019; Revised December 13, 2019; Accepted December 14, 2019.; Published online February 24, 2020.
© Korean Society for Molecular and Cellular Biology. All rights reserved.

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 isoleucyltRNA 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 Å 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.
Keywords: active site closure, aminoacyl-tRNA synthetases, anti-infective agents, crystal structure, mupirocin
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