Structural basis for the antibiotic resistance of eukaryotic isoleucyl-trna synthetase

Scisung Chung, Sulhee Kim, Sung Ho Ryu, Kwang Yeon Hwang, Yunje Cho

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)350-359
Number of pages10
JournalMolecules and cells
Volume43
Issue number4
DOIs
Publication statusPublished - 2020

Keywords

  • Active site closure
  • Aminoacyl-tRNA synthetases
  • Anti-infective agents
  • Crystal structure
  • Mupirocin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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