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Structural Basis for the Antibiotic Resistance of Eukaryotic Isoleucyl-tRNA Synthetase.
- Source :
-
Molecules and cells [Mol Cells] 2020 Apr 30; Vol. 43 (4), pp. 350-359. - Publication Year :
- 2020
-
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 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 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.
Details
- Language :
- English
- ISSN :
- 0219-1032
- Volume :
- 43
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecules and cells
- Publication Type :
- Academic Journal
- Accession number :
- 32088946
- Full Text :
- https://doi.org/10.14348/molcells.2020.2287