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?-Turn mimetic-based stabilizers of protein-protein interactions for the study of the non-canonical roles of leucyl-tRNA synthetase.

ABSTRACT: For the systematic perturbation of protein-protein interactions, we designed and synthesized tetra-substituted hexahydro-4H-pyrazino[2,1-c][1,2,4]triazine-4,7(6H)-diones as ?-turn mimetics. We then devised a new synthetic route to obtain ?-turn mimetic scaffolds via tandem N-acyliminium cyclization and constructed a 162-member library of tetra-substituted pyrazinotriazinediones with an average purity of 90% using a solid-phase parallel synthesis platform. Each library member was subjected to ELISA-based modulator screening for the LRS-RagD interaction, which plays a pivotal role in the nutrient-dependent mTORC1 signalling pathway. Western blot analysis of phosphorylated S6K1 as well as FRET-based imaging confirmed that 5c{3,9} stabilizes the direct interaction between LRS and RagD and activates mTORC1 in live cells under leucine-deprived conditions. Thus, 5c{3,9} can be used as a new research tool for studying the non-canonical role of LRS.

SUBMITTER: Kim C 

PROVIDER: S-EPMC5477029 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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β-Turn mimetic-based stabilizers of protein-protein interactions for the study of the non-canonical roles of leucyl-tRNA synthetase.

Kim Chanwoo C   Jung Jinjoo J   Tung Truong T TT   Park Seung Bum SB  

Chemical science 20151215 4

For the systematic perturbation of protein-protein interactions, we designed and synthesized tetra-substituted hexahydro-4<i>H</i>-pyrazino[2,1-<i>c</i>][1,2,4]triazine-4,7(6<i>H</i>)-diones as β-turn mimetics. We then devised a new synthetic route to obtain β-turn mimetic scaffolds <i>via</i> tandem <i>N</i>-acyliminium cyclization and constructed a 162-member library of tetra-substituted pyrazinotriazinediones with an average purity of 90% using a solid-phase parallel synthesis platform. Each  ...[more]

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