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@ARTICLE{Mojr:474132,
author = {Mojr, Viktor and Roghanian, Mohammad and Tamman, Hedvig and
Do Pham, Duy Dinh and Petrová, Magdalena and Pohl, Radek
and Takada, Hiraku and Van Nerom, Katleen and Ainelo, Hanna
and Caballero-Montes, Julien and Jimmy, Steffi and
Garcia-Pino, Abel and Hauryliuk, Vasili and Rejman, Dominik},
title = {{N}onhydrolysable {A}nalogues of (p)pp{G}pp and (p)pp{A}pp
{A}larmone {N}ucleotides as {N}ovel {M}olecular {T}ools},
journal = {ACS chemical biology},
volume = {16},
number = {9},
issn = {1554-8929},
address = {Washington, DC},
publisher = {Soc.},
reportid = {PUBDB-2022-00522},
pages = {1680 - 1691},
year = {2021},
note = {Waiting for fulltext},
abstract = {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) 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.},
cin = {CSSB-DESY-HS},
ddc = {540},
cid = {I:(DE-H253)CSSB-DESY-HS-20210521},
pnm = {633 - Life Sciences – Building Blocks of Life: Structure
and Function (POF4-633)},
pid = {G:(DE-HGF)POF4-633},
experiment = {EXP:(DE-MLZ)External-20140101},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34477366},
UT = {WOS:000697343400008},
doi = {10.1021/acschembio.1c00398},
url = {https://bib-pubdb1.desy.de/record/474132},
}