Fragment-based methods for the discovery of inhibitors modulating lysyl-tRNA synthetase and laminin receptor interaction

Hye Young Cho, Sunghoon Kim, Young Ho Jeon

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Lysyl-tRNA synthetase (KRS) is an enzyme that conjugates lysine to its cognate tRNAs in the process of protein synthesis. In addition to its catalytic function, KRS binds to the 67-kDa laminin receptor (LR) on the cell membrane and facilitates cell migration and metastasis. Modulation of this interaction by small-molecule inhibitors can be exploited to suppress cancer metastasis. In this study, we present fragment-based methods for the identification of inhibitors and monitoring protein–protein interactions between KRS and LR. First, we identified the amino acid residues, located on the KRS anticodon-binding domain, which interact with the C-terminal extension of the LR. One-dimensional (1D) relaxation-edited nuclear magnetic resonance spectroscopy (NMR) and competition experiments were designed and optimized to screen the fragment library. For screening using two-dimensional (2D) NMR, we identified the indicative signals in the KRS anticodon-binding domain and selected inhibitors that bind to KRS and compete with LR at the KRS-LR binding interface. These methods may offer an efficient approach for the discovery of anti-metastatic drugs.

Original languageEnglish
Pages (from-to)56-63
Number of pages8
JournalMethods
Volume113
DOIs
Publication statusPublished - 2017 Jan 15

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)

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