Transcription inhibition by the depsipeptide antibiotic salinamide A
Copyright policy )Transcription inhibition by the depsipeptide antibiotic salinamide A
We report that bacterial RNA polymerase (RNAP) is the functional cellular target of the depsipeptide antibiotic salinamide A (Sal), and we report that Sal inhibits RNAP through a novel binding site and mechanism. We show that Sal inhibits RNA synthesis in cells and that mutations that confer Sal-resistance map to RNAP genes. We show that Sal interacts with the RNAP active-center ‘bridge-helix cap’ comprising the ‘bridge-helix N-terminal hinge’, ‘F-loop’, and ‘link region’. We show that Sal inhibits nucleotide addition in transcription initiation and elongation. We present a crystal structure that defines interactions between Sal and RNAP and effects of Sal on RNAP conformation. We propose that Sal functions by binding to the RNAP bridge-helix cap and preventing conformational changes of the bridge-helix N-terminal hinge necessary for nucleotide addition. The results provide a target for antibacterial drug discovery and a reagent to probe conformation and function of the bridge-helix N-terminal hinge.
- University of California, San Diego United States
- Scripps Institution of Oceanography United States
- Rutgers, The State University of New Jersey United States
- Center for Advanced Biotechnology and Medicine United States
- University of California, San Francisco United States
Models, Molecular, Protein Structure, Secondary, Transcription, Genetic, QH301-705.5, Science, Molecular Sequence Data, bridge helix, Crystallography, X-Ray, Biochemistry, Protein Structure, Secondary, Genetic, Models, antibiotic, Depsipeptides, Genetics, Escherichia coli, Amino Acid Sequence, Biology (General), Enzyme Inhibitors, Crystallography, Nucleotides, Prevention, Q, R, 500, Molecular, DNA-Directed RNA Polymerases, 540, Bromine, Anti-Bacterial Agents, inhibitor, Protein Subunits, RNA polymerase, Mutation, X-Ray, bridge-helix cap, Medicine, Biochemistry and Cell Biology, transcription, Transcription
Models, Molecular, Protein Structure, Secondary, Transcription, Genetic, QH301-705.5, Science, Molecular Sequence Data, bridge helix, Crystallography, X-Ray, Biochemistry, Protein Structure, Secondary, Genetic, Models, antibiotic, Depsipeptides, Genetics, Escherichia coli, Amino Acid Sequence, Biology (General), Enzyme Inhibitors, Crystallography, Nucleotides, Prevention, Q, R, 500, Molecular, DNA-Directed RNA Polymerases, 540, Bromine, Anti-Bacterial Agents, inhibitor, Protein Subunits, RNA polymerase, Mutation, X-Ray, bridge-helix cap, Medicine, Biochemistry and Cell Biology, transcription, Transcription
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