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PDBsum entry 4a12
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Transcription
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PDB id
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4a12
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References listed in PDB file
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Key reference
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Title
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Structural basis for feed-Forward transcriptional regulation of membrane lipid homeostasis in staphylococcus aureus.
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Authors
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D.Albanesi,
G.Reh,
M.E.Guerin,
F.Schaeffer,
M.Debarbouille,
A.Buschiazzo,
G.E.Schujman,
D.De mendoza,
P.M.Alzari.
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Ref.
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Plos Pathog, 2013,
9,
e1003108.
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PubMed id
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Abstract
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The biosynthesis of membrane lipids is an essential pathway for virtually all
bacteria. Despite its potential importance for the development of novel
antibiotics, little is known about the underlying signaling mechanisms that
allow bacteria to control their membrane lipid composition within narrow limits.
Recent studies disclosed an elaborate feed-forward system that senses the levels
of malonyl-CoA and modulates the transcription of genes that mediate fatty acid
and phospholipid synthesis in many Gram-positive bacteria including several
human pathogens. A key component of this network is FapR, a transcriptional
regulator that binds malonyl-CoA, but whose mode of action remains enigmatic. We
report here the crystal structures of FapR from Staphylococcus aureus (SaFapR)
in three relevant states of its regulation cycle. The repressor-DNA complex
reveals that the operator binds two SaFapR homodimers with different affinities,
involving sequence-specific contacts from the helix-turn-helix motifs to the
major and minor grooves of DNA. In contrast with the elongated conformation
observed for the DNA-bound FapR homodimer, binding of malonyl-CoA stabilizes a
different, more compact, quaternary arrangement of the repressor, in which the
two DNA-binding domains are attached to either side of the central
thioesterase-like domain, resulting in a non-productive overall conformation
that precludes DNA binding. The structural transition between the DNA-bound and
malonyl-CoA-bound states of SaFapR involves substantial changes and large
(>30 Å) inter-domain movements; however, both conformational states can be
populated by the ligand-free repressor species, as confirmed by the structure of
SaFapR in two distinct crystal forms. Disruption of the ability of SaFapR to
monitor malonyl-CoA compromises cell growth, revealing the essentiality of
membrane lipid homeostasis for S. aureus survival and uncovering novel
opportunities for the development of antibiotics against this major human
pathogen.
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