ornithine decarboxylase inhibitor activity / transcription antitermination factor activity, RNA binding / misfolded RNA binding / Group I intron splicing / RNA folding / transcriptional attenuation / positive regulation of ribosome biogenesis / endoribonuclease inhibitor activity / RNA-binding transcription regulator activity / negative regulation of cytoplasmic translation ...ornithine decarboxylase inhibitor activity / transcription antitermination factor activity, RNA binding / misfolded RNA binding / Group I intron splicing / RNA folding / transcriptional attenuation / positive regulation of ribosome biogenesis / endoribonuclease inhibitor activity / RNA-binding transcription regulator activity / negative regulation of cytoplasmic translation / four-way junction DNA binding / DnaA-L2 complex / translation repressor activity / negative regulation of translational initiation / regulation of mRNA stability / negative regulation of DNA-templated DNA replication initiation / mRNA regulatory element binding translation repressor activity / assembly of large subunit precursor of preribosome / positive regulation of RNA splicing / ribosome assembly / transcription elongation factor complex / cytosolic ribosome assembly / regulation of DNA-templated transcription elongation / DNA endonuclease activity / response to reactive oxygen species / transcription antitermination / regulation of cell growth / DNA-templated transcription termination / maintenance of translational fidelity / response to radiation / mRNA 5'-UTR binding / regulation of translation / ribosome biogenesis / large ribosomal subunit / ribosome binding / transferase activity / ribosomal small subunit biogenesis / ribosomal small subunit assembly / small ribosomal subunit / small ribosomal subunit rRNA binding / 5S rRNA binding / ribosomal large subunit assembly / cytosolic small ribosomal subunit / large ribosomal subunit rRNA binding / cytosolic large ribosomal subunit / cytoplasmic translation / tRNA binding / negative regulation of translation / rRNA binding / ribosome / structural constituent of ribosome / translation / response to antibiotic / negative regulation of DNA-templated transcription / mRNA binding / DNA binding / RNA binding / zinc ion binding / membrane / cytosol / cytoplasm Similarity search - Function
Ribosomal protein S21, conserved site / Ribosomal protein S21 signature. / Ribosomal protein L25, short-form / Ribosomal protein S14, bacterial/plastid / Ribosomal protein S21 superfamily / Ribosomal protein S21 / Ribosomal protein S16, conserved site / Ribosomal protein S16 signature. / Ribosomal protein S21 / : ...Ribosomal protein S21, conserved site / Ribosomal protein S21 signature. / Ribosomal protein L25, short-form / Ribosomal protein S14, bacterial/plastid / Ribosomal protein S21 superfamily / Ribosomal protein S21 / Ribosomal protein S16, conserved site / Ribosomal protein S16 signature. / Ribosomal protein S21 / : / Ribosomal protein L16 signature 1. / Ribosomal protein L21, conserved site / Ribosomal protein L21 signature. / Ribosomal protein L16, conserved site / Ribosomal protein L16 signature 2. / Ribosomal protein L6, conserved site / Ribosomal protein L6 signature 1. / : / Ribosomal protein L17 signature. / Ribosomal L25p family / Ribosomal protein L25 / Ribosomal protein L36 signature. / Ribosomal protein L28/L24 superfamily / Ribosomal protein L32p, bacterial type / Ribosomal protein L25/Gln-tRNA synthetase, N-terminal / Ribosomal protein L25/Gln-tRNA synthetase, anti-codon-binding domain superfamily / Ribosomal protein L33, conserved site / Ribosomal protein L33 signature. / Ribosomal protein L35, conserved site / Ribosomal protein L35 signature. / : / Ribosomal protein L28 / Ribosomal protein L35, non-mitochondrial / Ribosomal protein L18, bacterial-type / : / Ribosomal protein L6, bacterial-type / Ribosomal protein S3, bacterial-type / Ribosomal protein S19, bacterial-type / Ribosomal protein S13, bacterial-type / Ribosomal protein S6, conserved site / Ribosomal protein S6 signature. / Ribosomal protein S7, bacterial/organellar-type / Ribosomal protein S9, bacterial/plastid / Ribosomal protein L36 / Ribosomal protein S11, bacterial-type / Ribosomal protein L36 superfamily / Ribosomal protein L36 / Ribosomal protein S20 / Ribosomal protein S20 superfamily / Ribosomal protein S20 / Ribosomal protein S4, bacterial-type / Ribosomal protein L19, conserved site / Ribosomal protein L19 signature. / 30S ribosomal protein S17 / Ribosomal protein S5, bacterial-type / Ribosomal protein L27, conserved site / Ribosomal protein L27 signature. / Ribosomal protein S6, plastid/chloroplast / Ribosomal protein L20 signature. / Ribosomal protein L22, bacterial/chloroplast-type / Ribosomal protein L14P, bacterial-type / Ribosomal protein S2, bacteria/mitochondria/plastid / Ribosomal protein L34, conserved site / Ribosomal protein L34 signature. / Ribosomal protein L2, bacterial/organellar-type / Ribosomal protein L35 / Ribosomal protein L35 superfamily / Ribosomal protein L35 / Ribosomal protein L33 / Ribosomal protein L33 / Ribosomal L28 family / Ribosomal protein L33 superfamily / Ribosomal protein L16 / Ribosomal protein L28/L24 / Ribosomal protein L18 / Ribosomal protein S18, conserved site / Ribosomal L18 of archaea, bacteria, mitoch. and chloroplast / Ribosomal protein S18 signature. / Ribosomal protein L30, bacterial-type / Ribosomal protein S16 / Ribosomal protein S16 domain superfamily / Ribosomal protein S16 / : / L28p-like / Ribosomal protein S15, bacterial-type / Ribosomal protein S6 / Ribosomal protein S6 / Ribosomal protein S6 superfamily / Ribosomal protein L27 / Ribosomal L27 protein / Ribosomal protein L20 / Ribosomal protein S12, bacterial-type / Ribosomal L32p protein family / Ribosomal protein L19 / Ribosomal protein L19 / Ribosomal protein L20 / Ribosomal protein L20, C-terminal / Ribosomal protein L19 superfamily / Ribosomal protein L21 / Translation elongation factor EF1B/ribosomal protein S6 Similarity search - Domain/homology
Small ribosomal subunit protein bS6 / Small ribosomal subunit protein uS7 / Large ribosomal subunit protein uL15 / Large ribosomal subunit protein bL19 / Large ribosomal subunit protein bL20 / Large ribosomal subunit protein bL27 / Large ribosomal subunit protein bL28 / Large ribosomal subunit protein uL29 / Large ribosomal subunit protein bL32 / Large ribosomal subunit protein bL33 ...Small ribosomal subunit protein bS6 / Small ribosomal subunit protein uS7 / Large ribosomal subunit protein uL15 / Large ribosomal subunit protein bL19 / Large ribosomal subunit protein bL20 / Large ribosomal subunit protein bL27 / Large ribosomal subunit protein bL28 / Large ribosomal subunit protein uL29 / Large ribosomal subunit protein bL32 / Large ribosomal subunit protein bL33 / Large ribosomal subunit protein bL34 / Large ribosomal subunit protein bL35 / Large ribosomal subunit protein bL36A / Small ribosomal subunit protein uS10 / Small ribosomal subunit protein uS11 / Small ribosomal subunit protein uS12 / Small ribosomal subunit protein uS13 / Small ribosomal subunit protein bS16 / Small ribosomal subunit protein bS18 / Small ribosomal subunit protein uS19 / Small ribosomal subunit protein bS20 / Small ribosomal subunit protein uS2 / Small ribosomal subunit protein uS3 / Small ribosomal subunit protein uS4 / Small ribosomal subunit protein uS5 / Small ribosomal subunit protein uS8 / Small ribosomal subunit protein uS9 / Large ribosomal subunit protein uL13 / Large ribosomal subunit protein uL14 / Large ribosomal subunit protein uL16 / Large ribosomal subunit protein uL23 / Small ribosomal subunit protein uS15 / Large ribosomal subunit protein bL17 / Large ribosomal subunit protein bL21 / Large ribosomal subunit protein uL30 / Large ribosomal subunit protein uL6 / Small ribosomal subunit protein uS14 / Small ribosomal subunit protein uS17 / Large ribosomal subunit protein uL18 / Large ribosomal subunit protein uL2 / Large ribosomal subunit protein uL3 / Large ribosomal subunit protein uL24 / Large ribosomal subunit protein uL4 / Large ribosomal subunit protein uL22 / Small ribosomal subunit protein bS21 / Large ribosomal subunit protein bL25 Similarity search - Component
Journal: J Am Chem Soc / Year: 2023 Title: The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition. Authors: Timm O Koller / Ullrich Scheid / Teresa Kösel / Jennifer Herrmann / Daniel Krug / Helena I M Boshoff / Bertrand Beckert / Joanna C Evans / Jan Schlemmer / Becky Sloan / Danielle M Weiner / ...Authors: Timm O Koller / Ullrich Scheid / Teresa Kösel / Jennifer Herrmann / Daniel Krug / Helena I M Boshoff / Bertrand Beckert / Joanna C Evans / Jan Schlemmer / Becky Sloan / Danielle M Weiner / Laura E Via / Atica Moosa / Thomas R Ioerger / Michael Graf / Boris Zinshteyn / Maha Abdelshahid / Fabian Nguyen / Stefan Arenz / Franziska Gille / Maik Siebke / Tim Seedorf / Oliver Plettenburg / Rachel Green / Anna-Luisa Warnke / Joachim Ullrich / Ralf Warrass / Clifton E Barry / Digby F Warner / Valerie Mizrahi / Andreas Kirschning / Daniel N Wilson / Rolf Müller / Abstract: Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum ...Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against . To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent.
Entire : Cryo-EM structure of the E.coli 70S ribosome in complex with the ...
Entire
Name: Cryo-EM structure of the E.coli 70S ribosome in complex with the antibiotic Myxovalargin B.
Components
Complex: Cryo-EM structure of the E.coli 70S ribosome in complex with the antibiotic Myxovalargin B.
RNA: 23S ribosomal RNA
RNA: 5S ribosomal RNA
Protein or peptide: 50S ribosomal protein L2
Protein or peptide: 50S ribosomal protein L3
Protein or peptide: 50S ribosomal protein L4
Protein or peptide: 50S ribosomal protein L6
Protein or peptide: 50S ribosomal protein L13
Protein or peptide: 50S ribosomal protein L14
Protein or peptide: 50S ribosomal protein L15
Protein or peptide: 50S ribosomal protein L16
Protein or peptide: 50S ribosomal protein L17
Protein or peptide: 50S ribosomal protein L18
Protein or peptide: 50S ribosomal protein L19
Protein or peptide: 50S ribosomal protein L20
Protein or peptide: 50S ribosomal protein L21
Protein or peptide: 50S ribosomal protein L22
Protein or peptide: 50S ribosomal protein L23
Protein or peptide: 50S ribosomal protein L24
Protein or peptide: 50S ribosomal protein L25
Protein or peptide: 50S ribosomal protein L27
Protein or peptide: 50S ribosomal protein L28
Protein or peptide: 50S ribosomal protein L29
Protein or peptide: 50S ribosomal protein L30
Protein or peptide: 50S ribosomal protein L32
Protein or peptide: 50S ribosomal protein L33
Protein or peptide: 50S ribosomal protein L34
Protein or peptide: 50S ribosomal protein L35
Protein or peptide: 50S ribosomal protein L36
RNA: P-tRNA fMet
RNA: 16S ribosomal RNA
Protein or peptide: 30S ribosomal protein S2
Protein or peptide: 30S ribosomal protein S3
Protein or peptide: 30S ribosomal protein S4
Protein or peptide: 30S ribosomal protein S5
Protein or peptide: 30S ribosomal protein S6
Protein or peptide: 30S ribosomal protein S7
Protein or peptide: 30S ribosomal protein S8
Protein or peptide: 30S ribosomal protein S9
Protein or peptide: 30S ribosomal protein S10
Protein or peptide: 30S ribosomal protein S11
Protein or peptide: 30S ribosomal protein S12
Protein or peptide: 30S ribosomal protein S13
Protein or peptide: 30S ribosomal protein S14
Protein or peptide: 30S ribosomal protein S15
Protein or peptide: 30S ribosomal protein S16
Protein or peptide: 30S ribosomal protein S17
Protein or peptide: 30S ribosomal protein S18
Protein or peptide: 30S ribosomal protein S19
Protein or peptide: 30S ribosomal protein S20
Protein or peptide: 30S ribosomal protein S21
RNA: messenger RNA
Protein or peptide: Myxovalargin B
Ligand: MAGNESIUM ION
Ligand: ZINC ION
Ligand: N-FORMYLMETHIONINE
Ligand: SPERMIDINE
Ligand: water
+
Supramolecule #1: Cryo-EM structure of the E.coli 70S ribosome in complex with the ...
Supramolecule
Name: Cryo-EM structure of the E.coli 70S ribosome in complex with the antibiotic Myxovalargin B. type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#51
Source (natural)
Organism: Escherichia coli BW25113 (bacteria)
Molecular weight
Theoretical: 2 MDa
+
Macromolecule #1: 23S ribosomal RNA
Macromolecule
Name: 23S ribosomal RNA / type: rna / ID: 1 / Number of copies: 1
Model: Quantifoil R2/2 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY / Support film - Film thickness: 20
Vitrification
Cryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
-
Electron microscopy
Microscope
FEI TITAN KRIOS
Image recording
Film or detector model: FEI FALCON II (4k x 4k) / Detector mode: COUNTING / Average electron dose: 2.5 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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