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Structural Basis for the Antibiotic Resistance Eukaryotic Isoleucyl-tRNA Synthetase SCIE SCOPUS KCI

Title
Structural Basis for the Antibiotic Resistance Eukaryotic Isoleucyl-tRNA Synthetase
Authors
Chung, ScisungKim, SulheeRyu, Sung HoHwang, Kwang YeonCho, Yunje
Date Issued
2020-04
Publisher
KOREAN SOC MOLECULAR & CELLULAR BIOLOGY
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.
URI
https://oasis.postech.ac.kr/handle/2014.oak/107903
DOI
10.14348/molcells.2020.2287
ISSN
1016-8478
Article Type
Article
Citation
MOLECULES AND CELLS, vol. 43, no. 4, page. 350 - 359, 2020-04
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류성호RYU, SUNG HO
Dept of Life Sciences
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