Fragment-based methods for the discovery of inhibitors modulating lysyl-tRNA synthetase and laminin receptor interaction
- Authors
- Cho, Hye Young; Kim, Sunghoon; Jeon, Young Ho
- Issue Date
- 15-Jan-2017
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Keywords
- Lysyl-tRNA synthetase; Laminin receptor; Cancer metastasis; Protein-protein interaction; Fragment-based drug discovery; Nuclear magnetic resonance (NMR)
- Citation
- METHODS, v.113, pp.56 - 63
- Indexed
- SCIE
SCOPUS
- Journal Title
- METHODS
- Volume
- 113
- Start Page
- 56
- End Page
- 63
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/84912
- DOI
- 10.1016/j.ymeth.2016.10.009
- ISSN
- 1046-2023
- Abstract
- Lysyl-tRNA synthetase (MRS) is an enzyme that conjugates lysine to its cognate tRNAs in the process of protein synthesis. In addition to its catalytic function, MRS 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 MRS 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 MRS anticodon-binding domain and selected inhibitors that bind to MRS and compete with LR at the MRS-LR binding interface. These methods may offer an efficient approach for the discovery of anti-metastatic drugs. (C) 2016 Published by Elsevier Inc.
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Collections - College of Pharmacy > Department of Pharmaceutical Science > 1. Journal Articles
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