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Open data
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Basic information
Entry | Database: PDB / ID: 6pc6 | |||||||||
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Title | E. coli 50S ribosome bound to compound 47 | |||||||||
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![]() | RIBOSOME / E. coli ribosome / streptogramin A analog / antibiotics | |||||||||
Function / homology | ![]() transcriptional attenuation / endoribonuclease inhibitor activity / RNA-binding transcription regulator activity / negative regulation of cytoplasmic translation / DnaA-L2 complex / translation repressor activity / negative regulation of DNA-templated DNA replication initiation / ribosome assembly / ribosomal large subunit assembly / DNA-templated transcription termination ...transcriptional attenuation / endoribonuclease inhibitor activity / RNA-binding transcription regulator activity / negative regulation of cytoplasmic translation / DnaA-L2 complex / translation repressor activity / negative regulation of DNA-templated DNA replication initiation / ribosome assembly / ribosomal large subunit assembly / DNA-templated transcription termination / mRNA 5'-UTR binding / large ribosomal subunit / transferase activity / large ribosomal subunit rRNA binding / cytosolic large ribosomal subunit / cytoplasmic translation / rRNA binding / negative regulation of translation / ribosome / structural constituent of ribosome / translation / response to antibiotic / negative regulation of DNA-templated transcription / mRNA binding / DNA binding / RNA binding / zinc ion binding / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.5 Å | |||||||||
![]() | Pellegrino, J. / Lee, D.J. / Fraser, J.S. / Seiple, I.B. | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Synthetic group A streptogramin antibiotics that overcome Vat resistance. Authors: Qi Li / Jenna Pellegrino / D John Lee / Arthur A Tran / Hector A Chaires / Ruoxi Wang / Jesslyn E Park / Kaijie Ji / David Chow / Na Zhang / Axel F Brilot / Justin T Biel / Gydo van Zundert ...Authors: Qi Li / Jenna Pellegrino / D John Lee / Arthur A Tran / Hector A Chaires / Ruoxi Wang / Jesslyn E Park / Kaijie Ji / David Chow / Na Zhang / Axel F Brilot / Justin T Biel / Gydo van Zundert / Kenneth Borrelli / Dean Shinabarger / Cindy Wolfe / Beverly Murray / Matthew P Jacobson / Estelle Mühle / Olivier Chesneau / James S Fraser / Ian B Seiple / ![]() ![]() ![]() Abstract: Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance ...Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics. Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins, potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome. Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed. Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. | |||||||||
History |
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Structure visualization
Movie |
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 1.6 MB | Display | ![]() |
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PDB format | ![]() | 1.2 MB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 20297MC ![]() 6pc5C ![]() 6pc7C ![]() 6pc8C ![]() 6pchC ![]() 6pcqC ![]() 6pcrC ![]() 6pcsC ![]() 6pctC ![]() 6wyvC ![]() 6x3cC ![]() 6x3jC M: map data used to model this data C: citing same article ( |
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Similar structure data | |
EM raw data | ![]() Data #1: Unaligned movies of 50S ribosome complex bound to compound 47 [micrographs - multiframe]) |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
-RNA chain , 2 types, 2 molecules IJ
#1: RNA chain | Mass: 941795.562 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#2: RNA chain | Mass: 38177.762 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-50S ribosomal protein ... , 5 types, 5 molecules KLMNO
#3: Protein | Mass: 29663.244 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
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#4: Protein | Mass: 15008.471 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#5: Protein | Mass: 22121.566 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#6: Protein | Mass: 22277.535 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
#7: Protein | Mass: 16050.606 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) ![]() ![]() |
-Non-polymers , 1 types, 1 molecules ![](data/chem/img/O7S.gif)
#8: Chemical | ChemComp-O7S / ( |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: 50S E. coli ribosome / Type: RIBOSOME / Entity ID: #1-#7 / Source: NATURAL |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 79.97 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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Symmetry | Point symmetry: C1 (asymmetric) |
3D reconstruction | Resolution: 2.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114964 / Symmetry type: POINT |