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PDBsum entry 5dec
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References listed in PDB file
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Key reference
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Title
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Catalytic mechanism and allosteric regulation of an oligomeric (p)ppgpp synthetase by an alarmone.
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Authors
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W.Steinchen,
J.S.Schuhmacher,
F.Altegoer,
C.D.Fage,
V.Srinivasan,
U.Linne,
M.A.Marahiel,
G.Bange.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
13348-13353.
[DOI no: ]
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PubMed id
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Abstract
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Nucleotide-based second messengers serve in the response of living organisms to
environmental changes. In bacteria and plant chloroplasts, guanosine
tetraphosphate (ppGpp) and guanosine pentaphosphate (pppGpp) [collectively named
"(p)ppGpp"] act as alarmones that globally reprogram cellular
physiology during various stress conditions. Enzymes of the RelA/SpoT homology
(RSH) family synthesize (p)ppGpp by transferring pyrophosphate from ATP to GDP
or GTP. Little is known about the catalytic mechanism and regulation of alarmone
synthesis. It also is unclear whether ppGpp and pppGpp execute different
functions. Here, we unravel the mechanism and allosteric regulation of the
highly cooperative alarmone synthetase small alarmone synthetase 1 (SAS1) from
Bacillus subtilis. We determine that the catalytic pathway of (p)ppGpp synthesis
involves a sequentially ordered substrate binding, activation of ATP in a
strained conformation, and transfer of pyrophosphate through a nucleophilic
substitution (SN2) reaction. We show that pppGpp-but not ppGpp-positively
regulates SAS1 at an allosteric site. Although the physiological significance
remains to be elucidated, we establish the structural and mechanistic basis for
a biological activity in which ppGpp and pppGpp execute different functional
roles.
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