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Rgg protein structure-function and inhibition by cyclic peptide compounds.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2015 Apr 21; Vol. 112 (16), pp. 5177-82. Date of Electronic Publication: 2015 Apr 06. - Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- Amino Acid Sequence
Binding Sites
Crystallography, X-Ray
Cyclosporine chemistry
Cyclosporine pharmacology
Cyclosporins pharmacology
Disulfides metabolism
Humans
Immunosuppressive Agents chemistry
Immunosuppressive Agents pharmacology
Models, Molecular
Molecular Sequence Data
Pheromones metabolism
Protein Binding drug effects
Protein Multimerization drug effects
Protein Structure, Tertiary
Protein Tyrosine Phosphatase, Non-Receptor Type 11 metabolism
Signal Transduction drug effects
Structure-Activity Relationship
Bacterial Proteins antagonists & inhibitors
Bacterial Proteins chemistry
Peptides, Cyclic pharmacology
Streptococcus metabolism
Trans-Activators antagonists & inhibitors
Trans-Activators chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 112
- Issue :
- 16
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 25847993
- Full Text :
- https://doi.org/10.1073/pnas.1500357112