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PDBsum entry 4yv6
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DNA binding protein
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PDB id
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4yv6
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References listed in PDB file
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Key reference
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Title
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Rgg protein structure-Function and inhibition by cyclic peptide compounds.
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Authors
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V.Parashar,
C.Aggarwal,
M.J.Federle,
M.B.Neiditch.
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Ref.
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Proc Natl Acad Sci U S A, 2015,
112,
5177-5182.
[DOI no: ]
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PubMed id
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Abstract
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Peptide pheromone cell-cell signaling (quorum sensing) regulates the expression
of diverse developmental phenotypes (including virulence) in Firmicutes, which
includes common human pathogens, e.g., Streptococcus pyogenes and Streptococcus
pneumoniae. Cytoplasmic transcription factors known as "Rgg proteins"
are peptide pheromone receptors ubiquitous in Firmicutes. Here we present X-ray
crystal structures of a Streptococcus Rgg protein alone and in complex with a
tight-binding signaling antagonist, the cyclic undecapeptide cyclosporin A. To
our knowledge, these represent the first Rgg protein X-ray crystal structures.
Based on the results of extensive structure-function analysis, we reveal the
peptide pheromone-binding site and the mechanism by which cyclosporin A inhibits
activation of the peptide pheromone receptor. Guided by the Rgg-cyclosporin A
complex structure, we predicted that the nonimmunosuppressive cyclosporin A
analog valspodar would inhibit Rgg activation. Indeed, we found that, like
cyclosporin A, valspodar inhibits peptide pheromone activation of conserved Rgg
proteins in medically relevant Streptococcus species. Finally, the crystal
structures presented here revealed that the Rgg protein DNA-binding domains are
covalently linked across their dimerization interface by a disulfide bond formed
by a highly conserved cysteine. The DNA-binding domain dimerization interface
observed in our structures is essentially identical to the interfaces previously
described for other members of the XRE DNA-binding domain family, but the
presence of an intermolecular disulfide bond buried in this interface appears to
be unique. We hypothesize that this disulfide bond may, under the right
conditions, affect Rgg monomer-dimer equilibrium, stabilize Rgg conformation, or
serve as a redox-sensitive switch.
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