Nonhydrolysable Analogues of (p)ppGpp and (p)ppApp Alarmone Nucleotides as Novel Molecular Tools
نویسندگان
چکیده
While alarmone nucleotides guanosine-3',5'-bisdiphosphate (ppGpp) and guanosine-5'-triphosphate-3'-diphosphate (pppGpp) are archetypical bacterial second messengers, their adenosine analogues ppApp (adenosine-3',5'-bisdiphosphate) pppApp (adenosine-5'-triphosphate-3'-diphosphate) toxic effectors that abrogate growth. The alarmones both synthesized degraded by the members of RelA-SpoT Homologue (RSH) enzyme family. Because chemical enzymatic liability (p)ppGpp (p)ppApp, these prone to degradation during structural biology experiments. To overcome this limitation, we have established an efficient straightforward procedure for synthesizing nonhydrolysable (p)ppNuNpp starting from 3'-azido-3'-deoxyribonucleotides as key intermediates. demonstrate utility (p)ppGNpp a molecular tool, show (i) HD substrate mimic, ppGNpp competes with ppGpp inhibit activity human MESH1 Small Alarmone Hyrolase, SAH; (ii) mimicking allosteric effects (p)ppGpp, acts positive regulator synthetase long ribosome-associated RSHs Rel RelA. Finally, solving structure N-terminal domain region (NTD) T. thermophilus complexed pppGNpp, analogue serves bona fide orthosteric promotes same intra-NTD rearrangements native substrate.
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ژورنال
عنوان ژورنال: ACS Chemical Biology
سال: 2021
ISSN: ['1554-8929', '1554-8937']
DOI: https://doi.org/10.1021/acschembio.1c00398