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000474132 1001_ $$aMojr, Viktor$$b0
000474132 245__ $$aNonhydrolysable Analogues of (p)ppGpp and (p)ppApp Alarmone Nucleotides as Novel Molecular Tools
000474132 260__ $$aWashington, DC$$bSoc.$$c2021
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000474132 520__ $$aWhile alarmone nucleotides guanosine-3′,5′-bisdiphosphate (ppGpp) and guanosine-5′-triphosphate-3′-diphosphate (pppGpp) are archetypical bacterial second messengers, their adenosine analogues ppApp (adenosine-3′,5′-bisdiphosphate) and pppApp (adenosine-5′-triphosphate-3′-diphosphate) are toxic effectors that abrogate bacterial growth. The alarmones are both synthesized and degraded by the members of the RelA-SpoT Homologue (RSH) enzyme family. Because of the chemical and enzymatic liability of (p)ppGpp and (p)ppApp, these alarmones are prone to degradation during structural biology experiments. To overcome this limitation, we have established an efficient and straightforward procedure for synthesizing nonhydrolysable (p)ppNuNpp analogues starting from 3′-azido-3′-deoxyribonucleotides as key intermediates. To demonstrate the utility of (p)ppGNpp as a molecular tool, we show that (i) as an HD substrate mimic, ppGNpp competes with ppGpp to inhibit the enzymatic activity of human MESH1 Small Alarmone Hyrolase, SAH; and (ii) mimicking the allosteric effects of (p)ppGpp, (p)ppGNpp acts as a positive regulator of the synthetase activity of long ribosome-associated RSHs Rel and RelA. Finally, by solving the structure of the N-terminal domain region (NTD) of T. thermophilus Rel complexed with pppGNpp, we show that as an HD substrate mimic, the analogue serves as a bona fide orthosteric regulator that promotes the same intra-NTD structural rearrangements as the native substrate.
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000474132 7001_ $$aRoghanian, Mohammad$$b1
000474132 7001_ $$aTamman, Hedvig$$b2
000474132 7001_ $$aDo Pham, Duy Dinh$$b3
000474132 7001_ $$aPetrová, Magdalena$$b4
000474132 7001_ $$aPohl, Radek$$b5
000474132 7001_ $$aTakada, Hiraku$$b6
000474132 7001_ $$aVan Nerom, Katleen$$b7
000474132 7001_ $$aAinelo, Hanna$$b8
000474132 7001_ $$aCaballero-Montes, Julien$$b9
000474132 7001_ $$0P:(DE-H253)PIP1096636$$aJimmy, Steffi$$b10
000474132 7001_ $$0P:(DE-H253)PIP1018533$$aGarcia-Pino, Abel$$b11$$eCorresponding author
000474132 7001_ $$0P:(DE-H253)PIP1095158$$aHauryliuk, Vasili$$b12$$eCorresponding author
000474132 7001_ $$0P:(DE-HGF)0$$aRejman, Dominik$$b13$$eCorresponding author
000474132 773__ $$0PERI:(DE-600)2221735-6$$a10.1021/acschembio.1c00398$$gVol. 16, no. 9, p. 1680 - 1691$$n9$$p1680 - 1691$$tACS chemical biology$$v16$$x1554-8929$$y2021
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